Liquisoft capsules

ABSTRACT

Described herein are oral pharmaceutical compositions suitable for chewing, sucking, or buccal dissolution comprising soft gel capsules and liquid fills, methods for making the same, and methods for treating subjects in need thereof with such capsules. In particular, oral pharmaceutical compositions comprising chewable, suckable, or dissolvable soft gel capsules with various flowable fill compositions are described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/722,196, filed on Dec. 20, 2019, which is a continuation of U.S.patent application Ser. No. 15/795,814, filed on Oct. 27, 2017, now U.S.Pat. No. 10,555,901, which is a continuation of U.S. patent applicationSer. No. 15/080,614, filed on Mar. 25, 2016, now U.S. Pat. No.9,867,779, which claims priority to U.S. Provisional Patent ApplicationNos. 62/138,468, filed on Mar. 26, 2015, and 62/236,297, filed on Oct.2, 2015, each of which is incorporated herein in its entirety by expressreference thereto.

TECHNICAL FIELD

Described herein are oral pharmaceutical compositions suitable forchewing, sucking, or buccal dissolution comprising soft gel capsules andliquid fills, methods for making the same, and methods for treatingsubjects in need thereof with such capsules. In particular, oralpharmaceutical compositions comprising chewable, suckable, ordissolvable soft gel capsules with various flowable fill compositionsare described.

BACKGROUND

Chewable dosage forms are typically manufactured as solids, such aschewable tablets, or elastic semi-solids such as chewing gums, moldedgels, or chewable soft gelatin capsules. While elastic semi-solid formsprovide better mouth feel and customer acceptance, chewable soft gelatincapsules (e.g., “soft gels”) have a benefit of being ingestible and candeliver accurate amounts of active ingredients to the oral cavity anddigestive system.

Soft gels have gained popularity and acceptance due to their elegant andclear gelatin shells. Furthermore, soft gel capsules are uniform,stable, dissolve quickly, allow for liquid formulations, and are easierfor most subjects to swallow.

Soft gel capsules are typically formed of a capsule shell encapsulatinga liquid matrix fill. Several types of soft gel capsules can be chewedby the user. See e.g., U.S. Pat. Nos. 6,258,380; 8,097,279; 8,241,665;8,414,916; and 8,765,174. Such chewable soft capsules are chewed by thesubject to release the fill contents into the mouth, instead ofswallowing the capsule with the fill still encapsulated within theshell. Often the fill of chewable soft capsules contains substantialamounts of gelatin giving the fill a semi-solid characteristic, ratherthan a true liquid character.

Although chewable soft capsules provide an effective dosage system, useracceptance has been limited by the organoleptic properties of thecapsules, which are sometimes criticized as being leathery or rubbery.Chewable soft capsules sometimes have a distinguishable differencebetween the shell and fill in terms of texture and mouth-feel. Someusers experience difficulty consuming the masticated sheath after theinternal fill has been released. In addition, chewable soft capsulestend to harden over time.

Thus, there is an unmet need for chewable soft capsule dosage formscomprising liquid fills, where the capsule shell can be chewed, sucked,or that dissolves in the mouth and releases the active ingredient in aliquid form in the oral cavity. Accordingly, it is desirable to developchewable soft gelatin capsules having desirable organoleptic propertiesthat can be sucked or that slowly dissolve in the mouth to releasepleasant-tasting or refreshing liquid fills.

SUMMARY

One embodiment described herein is an oral pharmaceutical compositionsuitable for chewing, sucking, or buccal dissolution comprising a softcapsule with a flowable fill comprising one or more activepharmaceutical ingredients, nutraceuticals, flavors, or refresheners.Exemplary embodiments are cough and cold over-the-counter (OTC)remedies; nonsteroidal anti-inflammatory drugs (NSAIDs) for treatingpain; nicotine satiation, nicotine-replacement therapy, or smokingcessation therapy; breath fresheners or treatments for halitosis;treatments for temporary discomforts of the stomach and gastrointestinaltract; or as a delivery means for any of the active pharmaceuticalsdescribed herein.

Another embodiment described herein is an oral pharmaceuticalcomposition suitable for chewing, sucking, or buccal dissolutioncomprising a shell encapsulating a matrix, the shell comprising: (a) oneor more film-forming polymers; (b) one or more plasticizers; (c) one ormore polymer modifiers; (d) one or more first sweeteners; (e) one ormore first solvents; (f) optionally, one or more excipients; and amatrix comprising: (g) one or more hydrophilic vehicles; (h) one or moreflavors; (i) one or more second sweeteners; (j) one or more secondsolvents; (k) one or more active pharmaceutical ingredients; and (l)optionally, one or more excipients. In one aspect describe herein, thefilm-forming polymer comprises one or more of gelatin, partiallyhydrolyzed gelatin, hydrolyzed gelatin, hydrolyzed collagen, orcombinations thereof. In another aspect describe herein, the plasticizercomprises one or more of glycerol, maltitol, mannitol, xylitol, lycasin,or combinations thereof. In another aspect describe herein, the polymermodifier comprises one or more of citric acid, acetic acid, lactic acid,malic acid, tartaric acid, or combinations thereof. In another aspectdescribe herein, the hydrophilic vehicle comprises propylene glycol,polyethylene glycol 400, polyvinylpyrrolidone K30, glycerin, sorbitol,xylitol, maltitol, or combinations thereof. In another aspect describeherein, the first sweetener comprises sucralose, aspartame, stevia,acesulfame potassium, xylitol, or combinations thereof. In anotheraspect describe herein, the flavoring comprises citric acid, lacticacid, sodium citrate, orange flavor, eucalyptol, peppermint oil, methylsalicylate, glycine, or combinations thereof. In another aspect describeherein, the second sweetener comprises mannitol, maltitol, xylitol,thaumatin, glycyrrhizic acid salts, acesulfame potassium, acesulfamesalts, sucralose, aspartame, stevia, or combinations thereof. In anotheraspect describe herein, the active pharmaceutical ingredient comprisesone or more of: astemizole, azelastine, azatadine, brompheniramine,carbinoxamine, cetirizine, chlorpheniramine, clemastine, cyproheptadine,desloratadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine,fexofenadine, hydroxyzine, levocetirizine, loratadine, phenindamine,pheniramine, phenyltoloxamine, promethazine, pyrilamine, terfenadine,tripelennamine, triprolidine, acetyl dihydrocodeine, benproperine,benzonatate, benzylmorphine, bibenzonium bromide, butamirate,butorphanol, carbetapentane, chlophedianol, clobutinol, clofedanol,cloperastine, codeine, dextromethorphan, dextromethorphan hydrobromide,diacetylmorphine, dibunate, dihydrocodeine, dimemorfan, dimethoxanate,diphenhydramine, dropropizine, droxypropine, ethylmorphine, fedrilate,glaucine, hydrocodone, hydromorphone, isoaminile, laudanum,levodropropizine, levomethadone, levopropoxyphene, meprotixol,methadone, morclofone, nepinalone, nicocodine, nicodicodine,normethadone, noscapine, oxeladin, oxolamine, pentoxyverine, pholcodine,pipazetate, piperidione, prenoxdiazine, tipepidine, zipeprol,acetylcysteine, althea root, ambroxol, antimony pentasulfide,bromhexine, carbocisteine, cineole, combinations, combinations,creosote, dembrexine hydrochloride, domiodol, dornase alfa, eprazinone,erdosteine, guaiacolsulfonate, guaifenesin, hederae helicis folium,ipecacuanha, letosteine, levo verbenone, mannitol, mesna, neltenexine,potassium iodide, senega, sobrerol, stepronin, tiopronin, tyloxapol,pseudoephedrine, cetirizine, loratadine, fexofenadine, diphenhydramine,levocetirizine, desloratadine, phenol, ethanol, thymol, eucalyptol,ethanol, methyl salicylate, chlorhexidine gluconate, cetylpyridiniumchloride, hexetidine, triclosan, hydrogen peroxide, domiphen bromide,bismuth subsalicylate, loperamide hydrochloride, aluminum hydroxide,magnesium hydroxide, magnesium aluminum silicate simethicone, aluminumcarbonate, calcium carbonate, sodium bicarbonate, hydrotalcite,magaldrate, cimetidine, famotidine, nizatidine, ranitidine,lansoprazole, omeprazole, esomeprazole, rabeprazole, pantoprazole,dexlansoprazole, diphenoxylate, dicyclomine, loperamide, rifaximin,alosetron, cholestyramine, linaclotide, lubiprostone, methylcellulose,polycarbophil, psyllium, mineral oil, glycerol, docusate sodium, sodiumbicarbonate, sodium phosphate, magnesium citrate, magnesium oxide,magnesium sulfate, bisacodyl, sennosides, senna, castor oil,alclometasone, amcinonide, beclometasone, betamethasone, budesonide,ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol,cortivazol, deflazacort, deoxycorticosterone, desonide desoximetasone,dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone,fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone,fluperolone, fluticasone, fluticasone propionate, fluprednidene,formocortal, halcinonide, halometasone, hydrocortisone aceponate,hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,medrysone, meprednisone, methylprednisolone, methylprednisoloneaceponate, mometasone furoate, paramethasone, prednicarbate, prednisone,prednisolone, prednylidene, rimexolone, tixocortol, triamcinolone,ulobetasol, 5-fluorouracil, 5-fluorodeoxyuridine, capecitabine, calciumsupplements, calcimimetics, cinacalcet, nicotine, nicotine polacrilex,bupropion, varenicline, disulfiram, calcium carbimide, acamprosate,naltrexone, buprenorphine, methadone, levacetylmethadol, lofexidine,betahistine, cinnarizine, flunarizine, acetylleucine, gangliosides,ganglioside derivatives, tirilazad, riluzole, xaliproden, hydroxybutyricacid, amifampridine, doxylamine, diphenhydramine hydrochloride,melatonin, 1-theanine, monofluorophosphate, lactoferrin, lysozyme,lactoperoxidase, glucose oxidase, mutanase, dextranase, glycerol,carbamide peroxide, sodium bicarbonate, hydrated silica, silicondioxide, polyvinylpyrrolidone, potassium nitrate, sodiummonofluorophosphate, sodium tripolyphosphate, strontium chloride,potassium nitrate, strontium acetate, strontium chloride, calcium sodiumphosphosilicate, benzocaine, lidocaine, clove oil, sodium bicarbonate,citric acid, tartaric acid, aspirin, ibuprofen, aceclofenac, acemetacin,aloxiprin, azapropazone, benorilate, bromfenac, carprofen, celecoxib,choline magnesium salicylate, diclofenac, diflunisal, etodolac,etoricoxib, fisalamine, fenbufen, fenoprofen, flurbiprofen, indometacin,ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, meclofenamicacid, mefenamic acid, meloxicam, metamizole, methyl salicylate,magnesium salicylate, nabumetone, naproxen, nimesulide, paracetamol,oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicylsalicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenicacid, tolmetin, valdecoxib, acetylsalicylic acid, aloxiprin,aminophenazone, anilides, benorilate, benzomorphan derivatives,bezitramide, bucetin, buprenorphine, butorphanol, carbasalate calcium,choline salicylate, codeine, dextromoramide, dextropropoxyphene,dezocine, diamorphine, diflunisal, dihydrocodeine, dihydrocodone,dihydromorphine, diphenylpropylamine derivatives, dipyrocetyl,ethenzamide, fentanyl, floctafenine, flupirtine, glafenine, guacetisal,hydrocodone, hydrocodone bitartrate, hydromorphone, hydromorphonehydrochloride, imidazole salicylate, ketobemidone, metamizole sodium,methadone, morphinan derivatives, morphine, morphine sulphatepentahydrate, morphine-6-glucuronode, morpholine salicylate, nalbuphine,natural opium alkaloids, nefopam, nicomorphine, nifenazone,non-steroidal anti-inflammatory drugs (NSAID), norhydrocodone,noroxycodone, opioids, opium, oripavine derivatives, oxycodeine,oxycodone, oxycodone hydrochloride, oxymorphone, papaveretum,pentazocine, pethidine, phenacetin, phenazocine, phenazone,phenylpiperidine derivatives, piritramide, potassium salicylate,propacetamol, propyphenazone, pyrazolones, rimazolium, salicylamide,salicylic acid derivatives, salsalate, sodium salicylate, tapentadol,tilidine, tramadol, viminol, ziconotide, caffeine, taurine, Ginkobiloba, glucuronolactone, inositol, niacin, niacinamide, D-pantothenol,Panax ginseng root extract, pyridoxine HCl, vitamin B12, cyanocobalamin,riboflavin, guarana, L-carnitine, vitamin A (retinol), B1 (thiamine), B2(riboflavin), B complex, B6 (pyridoxine), B12 (cobalamin), C (ascorbicacid), D (cholecalciferol), E (tocopherol), F (linoleic acid), G, H(biotin), and K, and choline, folic acid, inositol, niacin, pantothenicacid, para-aminobenzoic acid, terpenoids (e.g., carotenoid terpenoidsand non-carotenoid terpenoids), herbal supplements, homeopathicsupplements, glandular supplements, polyphenolics, flavonoidpolyphenolics, phenolic acids, curcumin, resveratrol, lignans,glucosinolates, isothiocyanates, indoles, thiosulfinates, phytosterols,anthraquinones, capsaicin, piperine, chlorophyll, betaine, oxalic acid,acetyl-L-carnitine, allantoin, androstenediol, androstendione, betaine(trimethylglycine), caffeine, calcium pyruvate (pyruvic acid),carnitine, carnosine, carotene, carotenoid, choline, chlorogenic acid,cholic acid, chondroitin sulfate, chondroitin sulfate, cholestan,chrysin, coenzyme Q10, conjugated linoleic acid, corosolic acid,creatine, dehydroepiandrosterone, dichlorophen, diindolymethane,dimethylglycine, dimercapto succinic acid, ebselen, ellagic acid,enzymes, fisetin, formononetin, glucaric acid (glucarate), glucosamine(HCl or sulfate), glucosamine (N-acetyl), glutathione, hesperidine,hydroxy-3-methylbutyric acid, 5-hydroxytryptophan, indole-3-carbinol,inositol, isothiocyanates, linolenic acid-gamma, lipoic acid (alpha),melatonin, methylsulfonylmethane, menthol, minerals, naringin,pancreatin, para-aminobenzoic acid, paraben (methyl or propyl),phenolics, phosphatidylcholine, phosphatidylserine, phospholipids,phytosterols, progesterone, pregnenolone, omega-3 fatty acids,quercetin, resveratrol, D-ribose, rutin, S-adenosylmethionine, salicylicacid, sulforaphane, tartaric acid, taxifolin, tetrahydropalmatine,theophyline, theobromine, tigogenin, troxerutin, tryptophan, tocotrienol(alpha, beta, and gamma), zeaxanthin, Gingko biloba, ginger, cat's claw,hypericum, Aloe vera, evening primrose, garlic, ginseng, capsicum, dongquai, ginseng, feverfew, fenugreek, echinacea, green tea, marshmallow,saw palmetto, tea tree oil, fish oil, psyllium, kava-kava, licoriceroot, Mahonia aquifolium, hawthorne, tumeric, witch Hazel, yohimbe,aleurain, mistletoe, bilberry, bee pollen, peppermint oil,beta-carotene, genistein, lutein, lycopene, polyphenols, Bifidobacteriuminfantis 35624, Bifidobacterium lactis HN019, Lactobacillus reuteriATCC55730, Lactobacillus rhamnosus, Lactobacillus casei DN-114 001,Bifidobacterium lactis Bb-12, or mixtures or combinations thereof. Inanother aspect describe herein, the excipients comprise one or moreflavorings, colorings, hygroscopic polymers, opacifiers, thickeningagents, surfactants, or pharmaceutically acceptable excipients. Inanother aspect describe herein, the one or more active pharmaceuticalingredients comprises one or more of dextromethorphan hydrobromide,menthol, thymol, nicotine, nicotine polacrilex, bismuth subsalicylate,NSAIDS, or combinations thereof. In another aspect describe herein, thematrix is a liquid, flowable gel, or viscous semi-solid. In anotheraspect describe herein, the shell comprises: (a) about 20% to about 60%of one or more film-forming polymers; (b) about 30% to about 70% of oneor more plasticizers; (c) about 0.5% to about 2% of one or more polymermodifiers; (d) about 0.1% to about 5% of one or more first sweeteners;and (e) about 10% to about 40% of one or more solvents. In anotheraspect describe herein, the matrix comprises: (a) about 30% to about 95%of one or more hydrophilic vehicles; (b) about 0.05% to about 5% of oneor more second sweeteners; (c) about 0.01% to about 6% of one or moreflavors; (d) about 1% to about 20% one or more solvents; and (e) about0.05% to about 60% of one or more active pharmaceutical ingredients. Inanother aspect describe herein, the shell comprises: (a) about 35% ofone or more film-forming polymers; (b) about 37% of one or moreplasticizers; (c) about 0.5% of one or more polymer modifiers; (d) about2.7% of one or more first sweeteners; and (e) about 21% of one or moresolvents. In another aspect describe herein, the ratio of the activepharmaceutical ingredient to a combined weight percentage of thehydrophilic vehicle, flavor, sweetener, solvent, and excipient is about1:0.5 to about 1:500.

Another embodiment described herein is method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,reducing the symptoms of, or promoting health, including but not limitedto of one or more of pain, inflammation, cough, cold, sinusitis, throator bronchial irritation, fever, flu, inflammation of thegastrointestinal tract, neoplasia, hyperthyroidism, hypercalcemia,hyperparathyroidism, parathyroid carcinoma, indigestion, heartburn,irritable bowels, constipation, diarrhea, insomnia, dry mouth,halitosis, stained teeth, oral pain, loss of enamel, cessation of urgeto smoke, fatigue, or malaise comprising administering to a subject inneed thereof any of the oral pharmaceutical compositions describedherein.

Another embodiment described herein is a composition for treating,retarding the progression of, prophylaxis of, delaying the onset of,ameliorating, reducing the symptoms of, or promoting health, includingbut not limited to of one or more of pain, inflammation, cough, cold,chest congestion, nasal congestion, sinusitis, throat or bronchialirritation, allergies, fever, flu, inflammation of the gastrointestinaltract, sour stomach, neoplasia, hyperthyroidism, hypercalcemia,hyperparathyroidism, parathyroid carcinoma, indigestion, heartburn,irritable bowels, constipation, diarrhea, insomnia, dry mouth, mouthodor, halitosis, stained teeth, oral pain, loss of enamel, nicotinedesire; cessation of urge to smoke, fatigue, or malaise comprisingadministering to a subject in need thereof any of the oralpharmaceutical compositions described herein.

Another embodiment described herein is a pharmaceutical compositioncomprising a soft dosage form comprising a shell encapsulating a liquidmatrix, wherein the shell comprises: (a) about 20% to about 60% of oneor more film-forming polymers; (b) about 30% to about 70% of one or moreplasticizers; (c) about 0.5% to about 2% of one or more polymermodifiers; (d) about 0.1% to about 5% of one or more first sweeteners;(e) about 10% to about 40% of one or more solvents; and the matrixcomprises: (f) about 30% to about 95% of one or more hydrophilicvehicles; (g) about 0.05% to about 5% of one or more second sweeteners;(h) about 0.01% to about 6% of one or more flavors; (i) about 1% toabout 20% water; and (j) about 0.05% to about 60% of one or more activepharmaceutical ingredients.

Another embodiment described herein is a method of delivering an activepharmaceutical ingredient to a patient population unable to receive aconventional dosage form comprising administering to the patient theoral pharmaceutical composition comprising a soft dosage form asdescribed herein.

Another embodiment described herein is a composition for delivering anactive pharmaceutical ingredient to a patient population unable toreceive a conventional dosage form comprising administering to thepatient in need thereof an oral pharmaceutical composition comprising asoft dosage form as described herein.

Another embodiment described herein is a pharmaceutical combinationcomprising any of the compositions described herein and one or moreadditional therapeutic compounds. In one aspect describe herein, the oneor more additional therapeutic compounds comprises one or more ofNSAIDS, diphenhydramine, codeine, chlorhexidine, cimetidine, ranitidine,famotidine, ondansetron, omeprazole, lansoprazole, rabeprazole,esomeprazole, pantoprazole, calcium supplements, magnesium hydroxide,bupropion, or varenicline.

Another embodiment described herein is a method for treating fortreating, retarding the progression of, prophylaxis of, delaying theonset of, ameliorating, reducing the symptoms of, or promoting health,including but not limited to of one or more of pain, inflammation,cough, cold, chest congestion, nasal congestion, sinusitis, throat orbronchial irritation, allergies, fever, flu, inflammation of thegastrointestinal tract, sour stomach, neoplasia, hyperthyroidism,hypercalcemia, hyperparathyroidism, parathyroid carcinoma, indigestion,heartburn, irritable bowels, constipation, diarrhea, insomnia, drymouth, mouth odor, halitosis, stained teeth, oral pain, loss of enamel,nicotine desire; cessation of urge to smoke, fatigue, or malaisecomprising administering to a subject in need thereof any of thepharmaceutical combinations described herein.

Another embodiment described herein is a method for manufacturing anoral pharmaceutical composition comprising the steps of: (a) preparing agel mass composition where the composition comprises one or more filmforming polymers, one or more plasticizers, one or more sweeteners, oneor more excipients in one or more solvents; (b) mixing the firstsolution at least about 50° C. under vacuum for 1 to 2 hours; (c)preparing a gel fill composition comprising one or more hydrophilicvehicles, one or more flavors, one or more sweeteners, one or moreexcipients, one or more active pharmaceutical ingredients in one or moresolvents; (d) mixing the second solution at least about 50° C.; (e)casting the gel composition into films or ribbons using heat-controlleddrums or surfaces; and (f) forming a soft dosage form comprising aliquid matrix fill using rotary die encapsulation technology.

Another embodiment described herein is an oral pharmaceuticalcomposition comprising a soft dosage form comprising an activepharmaceutical ingredient in a liquid matrix produced by any of themethods described herein. In one aspect described herein, the dosageform is stable for at 25° C. for at least one year.

Another embodiment described herein is a kit for dispensing any of theoral pharmaceutical compositions described herein comprising: (a) atleast one oral pharmaceutical composition; (b) at least one moistureproof dispensing receptacle comprising blister or strip packs, analuminum blister, a transparent or opaque polymer blister with pouch,polypropylene tubes, colored blister materials, tubes, bottles, andbottles optionally containing a child-resistant feature, optionallycomprising a desiccant, such as a molecular sieve or silica gel; andoptionally (c) at least one daily regimen for the oral pharmaceuticalcomposition; and (d) an insert comprising instructions or prescribinginformation for the oral pharmaceutical composition. In one aspectdescribed herein, the kit is useful for treating pain, inflammation,cough, cold, chest congestion, nasal congestion, sinusitis, throat orbronchial irritation, allergies, fever, flu, inflammation of thegastrointestinal tract, sour stomach, neoplasia, hyperthyroidism,hypercalcemia, hyperparathyroidism, parathyroid carcinoma, indigestion,heartburn, irritable bowels, constipation, diarrhea, insomnia, drymouth, mouth odor, halitosis, stained teeth, oral pain, loss of enamel,nicotine desire; cessation of urge to smoke, fatigue, or malaiseaccording to any of the methods described herein.

Another embodiment described herein is an oral pharmaceuticalcomposition suitable for chewing, sucking, or buccal dissolutioncomprising a shell encapsulating a matrix, the shell comprising: (a) oneor more film-forming polymers; (b) one or more plasticizers; (c) one ormore polymer modifiers; (d) one or more first sweeteners; (e) one ormore first solvents; and (f) optionally, one or more excipients; and thematrix comprising: (g) one or more hydrophilic vehicles; (h) one or moreflavors; (i) one or more second sweeteners; (j) one or more secondsolvents; (k) dextromethorphan hydrobromide; (l) menthol; and (m)optionally, one or more excipients. In one aspect described herein, thefilm-forming polymer comprises one or more of gelatin, partiallyhydrolyzed gelatin, hydrolyzed gelatin, hydrolyzed collagen, orcombinations thereof. In another aspect described herein, theplasticizer comprises one or more of glycerol, maltitol, mannitol,xylitol, lycasin, or combinations thereof. In another aspect describedherein, the polymer modifier comprises one or more of citric acid,acetic acid, lactic acid, malic acid, tartaric acid, or combinationsthereof. In another aspect described herein, the hydrophilic vehiclecomprises propylene glycol, polyethylene glycol 400,polyvinylpyrrolidone K30, glycerin, sorbitol, xylitol, maltitol, orcombinations thereof. In another aspect described herein, the firstsweetener comprises sucralose, aspartame, stevia, acesulfame potassium,xylitol, or combinations thereof. In another aspect described herein,the flavoring comprises citric acid, lactic acid, sodium citrate, orangeflavor, menthol, eucalyptol, peppermint oil, methyl salicylate, glycine,or combinations thereof. In another aspect described herein, the secondsweetener comprises mannitol, maltitol, xylitol, thaumatin, glycyrrhizicacid salts, acesulfame potassium, acesulfame salts, sucralose,aspartame, stevia, or combinations thereof. In another aspect describedherein, the excipients comprise one or more flavorings, colorings,hygroscopic polymers, opacifiers, thickening agents, surfactants, orpharmaceutically acceptable excipients. In another aspect describedherein, the matrix is a liquid, flowable gel, or viscous semi-solid. Inanother aspect described herein, the shell comprises: (a) about 10% toabout 80% of one or more film-forming polymers; (b) about 20% to about70% of one or more plasticizers; (c) about 0.01% to about 5% of one ormore polymer modifiers; (d) about 0.1% to about 5% of one or more firstsweeteners; (e) about 5% to about 50% of one or more first solvents; (f)optionally, one or more excipients; and the matrix comprises: (g) about40% to about 99% of one or more hydrophilic vehicles; (h) about 0.5% toabout 10% of one or more flavors; (i) about 0.5% to about 5% of one ormore second sweeteners; (j) about 1% to about 20% of one or more secondsolvents; (k) about 0.1% to about 5% of dextromethorphan hydrobromide;(l) about 0.05% to about 1% of menthol; and (m) optionally, one or moreexcipients. In another aspect described herein, the shell comprises: (a)about 10% to about 50% gelatin, 150 Bloom; (b) about 1% to about 20%gelatin, 100 Bloom; (c) about 1% to about 10% hydrolyzed collagen; (d)about 10% to about 20% lycasin; (e) about 10% to about 50% glycerin; (f)about 0.1% to about 2% citric acid; (g) about 0.1% to about 5% xylitol;(h) about 0.1% to about 1% sucralose; and (i) about 10% to about 50%water. In another aspect described herein, the matrix comprises: (a)about 10% to about 40% polyethylene glycol 400; (b) about 1% to about15% propylene glycol; (c) about 0.1% to about 5% polyvinylpyrrolidoneK30; (d) about 25% to about 75% lycasin; (e) about 0.1% to about 5%citric acid; (f) about 0.1% to about 5% lactic acid; (g) about 0.1% toabout 5% sucralose; (h) about 0.1% to about 5% acesulfame potassium; (i)about 1% to about 10% water; (j) about 0.1% to about 5% dextromethorphanhydrobromide; and (k) about 0.05% to about 1% menthol. In another aspectdescribed herein, the shell comprises: (a) about 20% gelatin, 150 Bloom;(b) about 9% gelatin, 100 Bloom; (c) about 5% hydrolyzed collagen; (d)about 17% lycasin; (e) about 25% glycerin; (f) about 0.5% citric acid;(g) about 2.5% about xylitol; (h) about 0.2% sucralose; and (i) about21% water; and the matrix comprises: (j) about 21% polyethylene glycol500; (k) about 8% propylene glycol; (l) about 1% polyvinylpyrrolidoneK30; (m) about 58% lycasin; (n) about 1% citric acid; (o) about 1%lactic acid; (p) about 0.6% sucralose; (q) about 0.6% acesulfamepotassium; (r) about 5% water; (s) about 1% dextromethorphanhydrobromide; and (t) about 0.1% menthol. In another aspect describedherein, the ratio of the active pharmaceutical ingredient to a combinedweight percentage of the hydrophilic vehicle, flavor, sweetener,solvent, and excipient is about 1:50 to about 1:200.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of, or promoting health, including but notlimited to of one or more of inflammation, cough, cold, chestcongestion, nasal congestion, sinusitis, throat or bronchial irritation,flu, fever, or pain comprising administering to a subject in needthereof any of the oral pharmaceutical compositions described herein.

Another embodiment described herein is a composition for treating,retarding the progression of, prophylaxis of, delaying the onset of,ameliorating, reducing the symptoms of, or promoting health, includingbut not limited to of one or more of, inflammation, cough, cold, chestcongestion, nasal congestion, sinusitis, throat or bronchial irritation,flu, fever, or pain comprising administering to a subject in needthereof any of the oral pharmaceutical compositions described herein.

Another embodiment described herein is a pharmaceutical compositioncomprising a soft dosage form comprising a shell encapsulating a liquidmatrix, wherein the shell comprises: (a) about 10% to about 50% gelatin,150 Bloom; (b) about 1% to about 20% gelatin, 100 Bloom; (c) about 1% toabout 10% hydrolyzed collagen; (d) about 10% to about 20% lycasin; (e)about 10% to about 50% glycerin; (f) about 0.1% to about 2% citric acid;(g) about 0.1% to about 5% xylitol; (h) about 0.1% to about 1%sucralose; and (i) about 10% to about 50% water; and the matrixcomprises: (j) about 10% to about 40% polyethylene glycol 400; (k) about1% to about 15% propylene glycol; (l) about 0.1% to about 5%polyvinylpyrrolidone K30; (m) about 25% to about 75% lycasin; (n) about0.1% to about 5% citric acid; (o) about 0.1% to about 5% lactic acid;(p) about 0.1% to about 5% sucralose; (q) about 0.1% to about 5%acesulfame potassium; (r) about 1% to about 10% water; (s) about 0.1% toabout 5% dextromethorphan hydrobromide; and (t) about 0.05% to about 1%menthol.

Another embodiment described herein is a method of delivering an activepharmaceutical ingredient to a patient population unable to receive aconventional dosage form comprising administering to the patient any ofthe oral pharmaceutical compositions described herein.

Another embodiment described herein is a composition for delivering anactive pharmaceutical ingredient to a patient population unable toreceive a conventional dosage form comprising administering to thepatient in need thereof any of the oral pharmaceutical compositionsdescribed herein.

Another embodiment described herein is a pharmaceutical combinationcomprising any one of the compositions described herein and one or moreadditional therapeutic compounds. In one aspect described herein, theone or more additional therapeutic compound comprises one or more ofNSAIDS, diphenhydramine, or codeine.

Another embodiment described herein is a method for treating fortreating, retarding the progression of, prophylaxis of, delaying theonset of, ameliorating, reducing the symptoms of, or promoting health,including but not limited to of one or more of inflammation, cough,cold, chest congestion, nasal congestion, sinusitis, throat or bronchialirritation, flu, fever, or pain comprising administering to a subject inneed thereof any of the pharmaceutical combinations described herein.

Another embodiment described herein is a pharmaceutical dosage form fortreating one or more of inflammation, cough, cold, chest congestion,nasal congestion, sinusitis, throat or bronchial irritation, flu, fever,or pain comprising any of the pharmaceutical compositions describedherein.

Another embodiment described herein is a method for treatinginflammation, cough, cold, chest congestion, nasal congestion,sinusitis, throat or bronchial irritation, flu, fever, or paincomprising administering one or more dosage forms comprising any of thepharmaceutical compositions described herein.

Another embodiment described herein is a means for treatinginflammation, cough, cold, chest congestion, nasal congestion,sinusitis, throat or bronchial irritation, flu, fever, or paincomprising administering one or more dosage forms comprising any of thepharmaceutical compositions described herein.

Another embodiment described herein is a method for manufacturing theoral pharmaceutical composition comprising the steps of: (a) preparing agel fill composition comprising a first solution and a second solutionwherein: (i) the first solution comprises polyvinylpyrrolidone K30,orange flavor, citric acid, sucralose, acesulfame potassium, lycasin andwater, one or more excipients in one or more solvents and mixed at atemperature no greater than 55° C. until dissolved and clear; (ii) thesecond solution comprises polyethylene glycol 400, propylene glycol andlactic acid and mixed until dissolved and clear; where the compositioncomprises one or more film forming polymers, one or more plasticizers,one or more sweeteners, one or more excipients in one or more solvents;(iii) adding dextromethorphan hydrobromide and menthol to the secondsolution and mixing the first solution and heating to no greater than55° C. until dissolved; and (iv) combining the first solution with thesecond solution and purging with nitrogen; (b) preparing a gel masscomposition comprising one or more film forming polymers, one or moreplasticizers, one or more sweeteners, one or more excipients and one ormore solvents; (c) casting the gel composition into films or ribbonsusing heat-controlled drums or surfaces; and (d) forming a soft dosageform comprising a liquid matrix fill using rotary die encapsulationtechnology.

Another embodiment described herein is a soft dosage form comprising anactive pharmaceutical ingredient in a liquid matrix produced by any ofthe methods described herein. In one aspect described herein, the dosageform is stable for at least 1 year at 25° C.

Another embodiment described herein is an oral pharmaceuticalcomposition suitable for chewing, sucking, or buccal dissolutioncomprising a shell encapsulating a matrix, the shell comprising: (a) oneor more film-forming polymers; (b) one or more plasticizers; (c) one ormore polymer modifiers; (d) one or more first sweeteners; (e) one ormore first solvents; and (f) optionally, one or more excipients; and thematrix comprising: (g) one or more hydrophilic vehicles; (h) one or moreflavors; (i) one or more second sweeteners; (j) one or more secondsolvents; (k) thymol; (l) menthol; and (m) optionally, one or moreexcipients. In one aspect described herein, the film-forming polymercomprises one or more of gelatin, partially hydrolyzed gelatin,hydrolyzed gelatin, hydrolyzed collagen, or combinations thereof. Inanother aspect described herein, the plasticizer comprises one or moreof glycerol, maltitol, mannitol, xylitol, lycasin, or combinationsthereof. In another acetic acid, malic acid, tartaric acid, orcombinations thereof. In another aspect described herein, thehydrophilic vehicle comprises propylene glycol, polyethylene glycol 400,polyvinylpyrrolidone K30, glycerin, sorbitol, xylitol, maltitol, orcombinations thereof. In another aspect described herein, the firstsweetener comprises sucralose, aspartame, stevia, acesulfame potassium,xylitol, or combinations thereof. In another aspect described herein,the flavoring comprises citric acid, lactic acid, sodium citrate, orangeflavor, eucalyptol, peppermint oil, methyl salicylate, glycine, orcombinations thereof. In another aspect described herein, the secondsweetener comprises mannitol, maltitol, xylitol, thaumatin, glycyrrhizicacid salts, acesulfame potassium, acesulfame salts, sucralose,aspartame, stevia, or combinations thereof. In another aspect describedherein, the excipients comprise one or more flavorings, colorings,hygroscopic polymers, opacifiers, thickening agents, surfactants, orpharmaceutically acceptable excipients. In another aspect describedherein, the matrix is a liquid, flowable gel, or viscous semi-solid. Inanother aspect described herein, the shell comprises: (a) about 10% toabout 80% of one or more film-forming polymers; (b) about 20% to about70% of one or more plasticizers; (c) about 0.01% to about 5% of one ormore polymer modifiers; (d) about 0.1% to about 5% of one or more firstsweeteners; (e) about 5% to about 50% of one or more first solvents; and(f) optionally, one or more excipients; and the matrix comprises: (g)about 50% to about 99% of one or more hydrophilic vehicles; (h) about0.01% to about 5% of one or more flavors; (i) about 0.01% to about 5% ofone or more second sweeteners; (j) about 1% to about 20% of one or moresecond solvents; (k) about 0.001% to about 1% of thymol; (l) about 0.05%to about 1% of menthol; and (m) optionally, one or more excipients. Inanother aspect described herein, the shell comprises: (a) about 10% toabout 40% gelatin, 100 Bloom; (b) about 1% to about 10% hydrolyzedcollagen; (c) about 10% to about 30% lycasin; (d) about 10% to about 40%glycerin; (e) about 1% to about 10% propylene glycol; (f) about 0.05% toabout 2% citric acid; (g) about 1% to about 5% xylitol; (h) about 0.05%to about 2% sucralose; (i) about 0.05% to about 2% peppermint oil; and(j) about 10% to about 40% water. In another aspect described herein,the matrix comprises: (a) about 30% to about 60% glycerin; (b) about0.05% to about 5% propylene glycol; (c) about 0.1% to about 5%polyvinylpyrrolidone K30; (d) about 20% to about 60% sorbitol; (e) about0.1% to about 5% citric acid; (f) about 0.1% to about 5% sucralose; (g)about 0.025% to about 2% eucalyptol; (h) about 0.05% to about 2%peppermint oil; (i) about 1% to about 20% water; (j) about 0.001% toabout 0.01% thymol; and (k) about 0.05% to about 3% menthol. In anotheraspect described herein, the shell comprises: (a) about 27% gelatin, 100Bloom; (b) about 5% hydrolyzed collagen; (c) about 17% lycasin; (e)about 21% glycerin; (f) about 1% propylene glycol; (g) about 0.5% citricacid; (h) about 2.5% xylitol; (i) about 0.8% sucralose; (j) about 0.1%peppermint oil; (k) about 24% water; and the matrix comprises: (l) about42% glycerin; (m) about 2% propylene glycol; (n) about 3%polyvinylpyrrolidone K30; (o) about 40% sorbitol; (p) about 0.3% citricacid; (q) about 0.5% sucralose; (r) about 0.1% eucalyptol; (s) about0.3% peppermint oil; (t) about 10% water; (u) about 0.004% thymol; and(v) about 0.2% menthol. In another aspect described herein, the ratio ofthe active pharmaceutical ingredient to a combined weight percentage ofthe hydrophilic vehicle, flavor, sweetener, solvent, and excipient isabout 1:250 to about 1:1000.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of, or promoting health, including but notlimited to of one or more of dry mouth, halitosis, stained teeth, oralpain, loss of enamel, refreshing breath, inhibiting onset of breathmalodor, or freshening the oral cavity comprising administering to asubject in need thereof any of the oral pharmaceutical compositionsdescribed herein.

Another embodiment described herein is a composition for treating,retarding the progression of, prophylaxis of, delaying the onset of,ameliorating, reducing the symptoms of, or promoting health, includingbut not limited to of one or more of dry mouth, halitosis, stainedteeth, oral pain, loss of enamel, refreshing breath, inhibiting onset ofbreath malodor, or freshening the oral cavity comprising administeringto a subject in need thereof any of the oral pharmaceutical compositionsdescribed herein.

Another embodiment described herein is a pharmaceutical compositioncomprising a soft dosage form comprising a shell encapsulating a liquidmatrix, wherein the shell comprises: (a) about 10% to about 40% gelatin,100 Bloom; (b) about 1% to about 10% hydrolyzed collagen; (c) about 10%to about 30% lycasin; (d) about 10% to about 40% glycerin; (e) about 1%to about 10% propylene glycol; (f) about 0.05% to about 2% citric acid;(g) about 1% to about 5% xylitol; (h) about 0.05% to about 2% sucralose;(i) about 0.05% to about 2% peppermint oil; and (j) about 10% to about40% water; and the matrix comprises: (k) about 30% to about 60%glycerin; (l) about 0.05% to about 5% propylene glycol; (m) about 0.1%to about 5% polyvinylpyrrolidone K30; (n) about 20% to about 60%sorbitol; (o) about 0.1% to about 5% citric acid; (p) about 0.1% toabout 5% sucralose; (q) about 0.025% to about 2% eucalyptol; (r) about0.05% to about 2% peppermint oil; (s) about 1% to about 20% water; (t)about 0.001% to about 0.01% thymol; and (u) about 0.05% to about 3%menthol.

Another embodiment described herein is a method of delivering an activepharmaceutical ingredient to a patient population unable to receive aconventional dosage form comprising administering to the patient theoral pharmaceutical composition comprising any of the soft dosage formsdescribed herein.

Another embodiment described herein is a composition for delivering anactive pharmaceutical ingredient to a patient population unable toreceive a conventional dosage form comprising administering to thepatient in need thereof an oral pharmaceutical composition comprisingany of the soft dosage forms described herein.

Another embodiment described herein is a pharmaceutical combinationcomprising any one of the compositions described herein and one or moreadditional therapeutic compounds. In one aspect described herein, theone or more additional therapeutic compounds comprises chlorhexidine orethanol.

Another embodiment described herein is a method for treating fortreating, retarding the progression of, prophylaxis of, delaying theonset of, ameliorating, reducing the symptoms of, or promoting health,including but not limited to of one or more of dry mouth, halitosis,stained teeth, oral pain, loss of enamel, refreshing breath, inhibitingonset of breath malodor, or freshening the oral cavity comprisingadministering to a subject in need thereof any of the pharmaceuticalcombinations described herein.

Another embodiment described herein is a pharmaceutical dosage form forrefreshing breath, inhibiting onset of breath malodor, treatinghalitosis, or freshening the oral cavity comprising any of thepharmaceutical compositions described herein.

Another embodiment described herein is a method for refreshing breath,inhibiting onset of breath malodor, treating halitosis, or fresheningthe oral cavity comprising administering one or more dosage formscomprising any of the pharmaceutical compositions described herein.

Another embodiment described herein is a means for refreshing breath,inhibiting onset of breath malodor, treating halitosis, or fresheningthe oral cavity comprising administering one or more dosage formscomprising any of the pharmaceutical compositions described herein.

Another embodiment described herein is a method for manufacturing anoral pharmaceutical composition comprising the steps of: (a) preparing agel fill composition comprising a first gel fill solution and a secondgel fill solution, wherein (i) the first gel fil solution comprises oneor more hydrophilic vehicle, sweetener, flavor, thymol, in one or moresolvents and is mixed at a temperature between 30-50° C. untildissolved; (ii) the second gel fill solution comprises one or morehydrophilic vehicles and menthol and is mixed at a temperature between30-50° C. until dissolved; and (iv) combining the first gel fillsolution and the second gel fill solution, adding flavor and mixing forat least 25 minutes; (b) preparing a gel mass composition comprising oneor more film forming polymers, one or more plasticizers, one or moresweeteners, one or more excipients and one or more solvents; (c) castingthe gel composition into films or ribbons using heat-controlled drums orsurfaces; and (d) forming a soft dosage form comprising a liquid matrixfill using rotary die encapsulation technology.

Another embodiment described herein is a soft dosage form comprising anactive pharmaceutical ingredient in a liquid matrix produced by any ofthe methods described herein. In one aspect described herein, the dosageform is stable for at least 1 year at 25° C.

Another embodiment described herein is an oral pharmaceuticalcomposition suitable for chewing, sucking, or buccal dissolutioncomprising a shell encapsulating a matrix, the shell comprising: (a) oneor more film-forming polymers; (b) one or more plasticizers; (c) one ormore polymer modifiers; (d) one or more first sweeteners; (e) one ormore first solvents; and (f) optionally, one or more excipients; and thematrix comprising: (g) one or more hydrophilic vehicles; (h) one or moreflavors; (i) one or more second sweeteners; (j) one or more secondsolvents; (k) nicotine polacrilex; and (l) optionally, one or moreexcipients. In one aspect described herein, the film-forming polymercomprises one or more of gelatin, partially hydrolyzed gelatin,hydrolyzed gelatin, hydrolyzed collagen, or combinations thereof. Inanother aspect described herein, the plasticizer comprises one or moreof glycerol, maltitol, mannitol, xylitol, lycasin, or combinationsthereof. In one aspect described herein, the polymer modifier comprisesone or more of citric acid, acetic acid, lactic acid, malic acid,tartaric acid, or combinations thereof. In one aspect described herein,the hydrophilic vehicle comprises propylene glycol, polyethylene glycol400, polyvinylpyrrolidone K30, glycerin, sorbitol, xylitol, maltitol, orcombinations thereof. In one aspect described herein, the firstsweetener comprises sucralose, aspartame, stevia, acesulfame potassium,xylitol, or combinations thereof. In one aspect described herein, theflavoring comprises citric acid, lactic acid, sodium citrate, orangeflavor, eucalyptol, peppermint oil, methyl salicylate, glycine, orcombinations thereof. In one aspect described herein, the secondsweetener comprises mannitol, maltitol, xylitol, thaumatin, glycyrrhizicacid salts, acesulfame potassium, acesulfame salts, sucralose,aspartame, stevia, or combinations thereof. In one aspect describedherein, the excipients comprise one or more flavorings, colorings,hygroscopic polymers, opacifiers, thickening agents, surfactants, orpharmaceutically acceptable excipients. In one aspect described herein,the matrix is a liquid, flowable gel, or viscous semi-solid. In oneaspect described herein, the shell comprises: (a) about 20% to about 80%of one or more film-forming polymers; (b) about 20% to about 70% of oneor more plasticizers; (c) about 0.01% to about 5% of one or more polymermodifiers; (d) about 0.1% to about 5% of one or more first sweeteners;(e) about 5% to about 50% of one or more first solvents; (f) optionally,one or more excipients; and the matrix comprises: (g) about 30% to about80% of one or more hydrophilic vehicles; (h) about 0.5% to about 10% ofone or more flavors; (i) about 0.01% to about 5% of one or more secondsweeteners; (j) about 1% to about 30% of one or more second solvents;(k) about 0.1% to about 5% of nicotine polacrilex; and (m) optionally,one or more excipients. In one aspect described herein, the shellcomprises: (a) about 10% to about 40% gelatin, 150 Bloom; (b) about 1%to about 20% gelatin, 100 Bloom; (c) about 1% to about 10% gelatinhydrolysate; (d) about 10% to about 40% glycerin; (e) about 10% to about40% maltitol; (f) about 0.05% to about 2% citric acid; (g) about 1% toabout 5% xylitol; (h) about 0.05% to about 2% sucralose; (i) about 0.05%to about 2% peppermint oil; and (j) about 10% to about 40% water. Inanother aspect described herein, the matrix comprises: (a) about 0.05%to about 5% polyethylene glycol 400; (b) about 10% to about 40%glycerin; (c) about 0.1% to about 5% xylitol; (d) about 10% to about 60%maltitol; (e) about 0.1% to about 10% glycine; (f) about 0.1% to about5% sucralose; (g) about 0.025% to about 2% menthol; (h) about 0.025% toabout 2% peppermint oil; (i) about 1% to about 30% water; and (j) about0.01% to about 5% nicotine polacrilex. In another aspect describedherein, the shell comprises: (a) about 22% gelatin, 150 Bloom; (b) about10% gelatin, 100 Bloom; (c) about 5% gelatin hydrolysate; (d) about 20%glycerin; (e) about 17% maltitol; (f) about 0.5% citric acid; (g) about2.6% xylitol; (h) about 0.2% sucralose; (i) about 0.3% peppermint oil;and (j) about 21% water; and the matrix comprises: (k) about 1%polyethylene glycol 400; (l) about 19% glycerin; (m) about 3% xylitol;(n) about 37% maltitol; (o) about 5% glycine; (p) about 0.2% sucralose;(q) about 0.04% menthol; (r) about 0.04% peppermint oil; (s) about 17%water; and (t) about 2% nicotine polacrilex. In another aspect describedherein, the ratio of the active pharmaceutical ingredient to a combinedweight percentage of the hydrophilic vehicle, flavor, sweetener,solvent, and excipient is about 1:10 to about 1:100.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of, or promoting health, including but notlimited to cessation of urge to smoke, satiating nicotine desire,nicotine-replacement therapy, or smoking cessation therapy comprisingadministering to a subject in need thereof any of the oralpharmaceutical compositions described herein.

Another embodiment described herein is a composition for treating,retarding the progression of, prophylaxis of, delaying the onset of,ameliorating, reducing the symptoms of, or promoting health, includingbut not limited to cessation of urge to smoke, satiating nicotinedesire, nicotine-replacement therapy, or smoking cessation therapycomprising administering to a subject in need thereof any of the oralpharmaceutical compositions described herein.

Another embodiment described herein is a pharmaceutical compositioncomprising a soft dosage form comprising a shell encapsulating a liquidmatrix, wherein the shell comprises: (a) about 10% to about 40% gelatin,150 Bloom; (b) about 1% to about 20% gelatin, 100 Bloom; (c) about 1% toabout 10% gelatin hydrolysate; (d) about 10% to about 40% glycerin; (e)about 10% to about 40% maltitol; (f) about 0.05% to about 2% citricacid; (g) about 1% to about 5% xylitol; (h) about 0.05% to about 2%sucralose; (i) about 0.05% to about 2% peppermint oil; and (j) about 10%to about 40% water; and the matrix comprises: (k) about 0.05% to about5% polyethylene glycol 400; (l) about 10% to about 40% glycerin; (m)about 0.1% to about 5% xylitol; (n) about 10% to about 60% maltitol; (o)about 0.1% to about 10% glycine; (p) about 0.1% to about 5% sucralose;(q) about 0.025% to about 2% menthol; (r) about 0.025% to about 2%peppermint oil; (s) about 1% to about 30% water; and (t) about 0.01% toabout 5% nicotine polacrilex.

Another embodiment described herein is a method of delivering an activepharmaceutical ingredient to a patient population unable to receive aconventional dosage form comprising administering to the patient theoral pharmaceutical composition comprising any of the soft dosage formsdescribed herein.

Another embodiment described herein is a composition for delivering anactive pharmaceutical ingredient to a patient population unable toreceive a conventional dosage form comprising administering to thepatient in need thereof an oral pharmaceutical composition comprisingany of the soft dosage forms described herein.

Another embodiment described herein is a pharmaceutical combinationcomprising any of the compositions described herein and one or moreadditional therapeutic compounds. In one aspect described herein, theone or more additional therapeutic compound comprises bupropion orvarenicline.

Another embodiment described herein is a method for treating fortreating, retarding the progression of, prophylaxis of, delaying theonset of, ameliorating, reducing the symptoms of, or promoting health,including but not limited to cessation of urge to smoke, satiatingnicotine desire, nicotine-replacement therapy, or smoking cessationtherapy comprising administering to a subject in need thereof any of thepharmaceutical combinations described herein.

Another embodiment described herein is a pharmaceutical dosage form forsatiating nicotine desire, nicotine-replacement therapy, or smokingcessation therapy comprising any of the pharmaceutical compositionsdescribed herein.

Another embodiment described herein is a method for satiating nicotinedesire, nicotine-replacement therapy, or smoking cessation therapycomprising administering one or more dosage forms comprising any of thepharmaceutical compositions described herein.

Another embodiment described herein is a means for satiating nicotinedesire, nicotine-replacement therapy, or smoking cessation therapycomprising administering one or more dosage forms comprising any of thepharmaceutical compositions described herein.

Another embodiment described herein is a method for manufacturing anoral pharmaceutical composition comprising the steps of: (a) preparing agel fill composition comprising a first solution, a flavor solution, anda sweetener solution wherein: (i) the first solution comprises one ormore hydrophilic vehicles, thickening agents, flavors, and excipientsand is mixed at a temperature between 30-70° C. until dissolved; (ii)the flavor solution comprises one or more hydrophilic vehicle and flavorand is mixed at a temperature between 30-70° C. until dissolved; (iii)the sweetener solution comprises one or more sweetener in one or moresolvents and nicotine and mixing until dissolved; and (iv) combining thefirst solution, flavor solution and sweetener solution and mixing tohomogenize; (b) preparing a gel mass composition comprising one or morefilm forming polymers, one or more plasticizers, one or more sweeteners,one or more excipients and one or more solvents; (c) casting the gelcomposition into films or ribbons using heat-controlled drums orsurfaces; and (d) forming a soft dosage form comprising a liquid matrixfill using rotary die encapsulation technology.

Another embodiment described herein is a soft dosage form comprising anactive pharmaceutical ingredient in a liquid matrix produced by any ofthe methods described herein. In one aspect described herein, the dosageform is stable for at least 1 year at 25° C.

Another embodiment described herein is an oral pharmaceuticalcomposition suitable for chewing, sucking, or buccal dissolutioncomprising a shell encapsulating a matrix, the shell comprising: (a) oneor more film-forming polymers; (b) one or more plasticizers; (c) one ormore polymer modifiers; (d) one or more first sweeteners; (e) one ormore first solvents; and (f) optionally, one or more excipients; and thematrix comprising: (g) one or more hydrophilic vehicles; (h) one or moreflavors; (i) one or more second sweeteners; (j) one or more secondsolvents; (k) bismuth subsalicylate; and (l) optionally, one or moreexcipients. In one aspect described herein, the film-forming polymercomprises one or more of gelatin, partially hydrolyzed gelatin,hydrolyzed gelatin, hydrolyzed collagen, or combinations thereof. Inanother aspect described herein, the plasticizer comprises one or moreof glycerol, maltitol, mannitol, xylitol, lycasin, or combinationsthereof. In another aspect described herein, the polymer modifiercomprises one or more of citric acid, acetic acid, lactic acid, malicacid, tartaric acid, or combinations thereof. In another aspectdescribed herein, the hydrophilic vehicle comprises propylene glycol,polyethylene glycol 400, polyvinylpyrrolidone K30, glycerin, sorbitol,xylitol, maltitol, or combinations thereof. In another aspect describedherein, the first sweetener comprises sucralose, aspartame, stevia,acesulfame potassium, xylitol, or combinations thereof. In anotheraspect described herein, the flavoring comprises citric acid, lacticacid, sodium citrate, orange flavor, eucalyptol, peppermint oil, methylsalicylate, glycine, or combinations thereof. In another aspectdescribed herein, the second sweetener comprises mannitol, maltitol,xylitol, thaumatin, glycyrrhizic acid salts, acesulfame potassium,acesulfame salts, sucralose, aspartame, stevia, or combinations thereof.In another aspect described herein, the excipients comprise one or moreflavorings, colorings, hygroscopic polymers, opacifiers, thickeningagents, surfactants, or pharmaceutically acceptable excipients. Inanother aspect described herein, the matrix is a liquid, flowable gel,or viscous semi-solid. In another aspect described herein, the shellcomprises: (a) about 10% to about 50% of one or more film-formingpolymers; (b) about 10% to about 60% of one or more plasticizers; (c)about 0.01% to about 5% of one or more polymer modifiers; (d) about 0.1%to about 5% of one or more first sweeteners; (e) about 5% to about 50%of one or more first solvents; and (f) optionally, one or moreexcipients; and the matrix comprises: (g) about 20% to about 70% of oneor more hydrophilic vehicles; (h) about 0.05% to about 1% of one or moreflavors; (i) about 0.25% to about 5% of one or more second sweeteners;(j) about 1% to about 20% of one or more second solvents; (k) about 20%to about 80% of bismuth subsalicylate; and (l) optionally, one or moreexcipients. In another aspect described herein, the shell comprises: (a)about 10% to about 40% gelatin, 150 Bloom; (b) about 1% to about 20%gelatin, 100 Bloom; (c) about 1% to about 10% gelatin hydrolysate; (d)about 10% to about 40% glycerin; (e) about 10% to about 40% maltitol;(f) about 0.05% to about 2% citric acid; (g) about 1% to about 5%xylitol; (h) about 0.05% to about 2% sucralose; and (i) about 10% toabout 40% water. In another aspect described herein, the matrixcomprises: (a) about 0.05% to about 5% polyethylene glycol 400; (b)about 0.5% to about 5% glycerin; (c) about 1% to about 15% propyleneglycol; (d) about 10% to about 40% sorbitol; (e) about 0.1% to about 5%xylitol; (f) about 0.05% to about 5% sucralose; (g) about 0.025% toabout 2% menthol; (h) about 0.025% to about 2% peppermint oil; (i) about1% to about 20% water; and (j) about 20% to about 80% bismuthsubsalicylate. In another aspect described herein, the shell comprises:(a) about 19% gelatin, 150 Bloom; (b) about 13% gelatin, 100 Bloom; (c)about 2% gelatin hydrolysate; (d) about 22% glycerin; (e) about 14%maltitol; (f) about 0.5% citric acid; (g) about 2.5% xylitol; (h) about0.2% sucralose; and (i) about 29% water; and the matrix comprises: (j)about 1% polyethylene glycol 400; (k) about 2% glycerin; (l) about 6%propylene glycol; (m) about 27% sorbitol; (n) about 3% xylitol; (o)about 0.2% sucralose; (p) about 0.04% menthol; (q) about 0.04%peppermint oil; (r) about 11% water; and (s) about 47% bismuthsubsalicylate. In another aspect described herein, the ratio of theactive pharmaceutical ingredient to a combined weight percentage of thehydrophilic vehicle, flavor, sweetener, solvent, and excipient is about1:0.01 to about 1:20.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of, or promoting health, including but notlimited to of one or more of inflammation of the gastrointestinal tract,neoplasia, hyperthyroidism, hypercalcemia, hyperparathyroidism,parathyroid carcinoma, indigestion, heartburn, nausea, flatulence,bloating, acid reflux, irritable bowels, constipation, diarrhea,comprising administering to a subject in need thereof any of the oralpharmaceutical compositions described herein.

Another embodiment described herein is a pharmaceutical compositioncomprising a soft dosage form comprising a shell encapsulating a liquidmatrix, wherein the shell comprises: (a) about 10% to about 40% gelatin,150 Bloom; (b) about 1% to about 20% gelatin, 100 Bloom; (c) about 1% toabout 10% gelatin hydrolysate; (d) about 10% to about 40% glycerin; (e)about 10% to about 40% maltitol; (f) about 0.05% to about 2% citricacid; (g) about 1% to about 5% xylitol; (h) about 0.05% to about 2%sucralose; and (i) about 10% to about 40% water; and the matrixcomprises: (j) about 0.05% to about 5% polyethylene glycol 400; (k)about 0.5% to about 5% glycerin; (l) about 1% to about 15% propyleneglycol; (m) about 10% to about 40% sorbitol; (n) about 0.1% to about 5%xylitol; (o) about 0.05% to about 5% sucralose; (p) about 0.025% toabout 2% menthol; (q) about 0.025% to about 2% peppermint oil; (r) about1% to about 20% water; and (s) about 20% to about 80% bismuthsubsalicylate.

Another embodiment described herein is a method of delivering an activepharmaceutical ingredient to a patient population unable to receive aconventional dosage form comprising administering to the patient theoral pharmaceutical composition comprising any of the soft dosage formsdescribed herein.

Another embodiment described herein is a composition for delivering anactive pharmaceutical ingredient to a patient population unable toreceive a conventional dosage form comprising administering to thepatient in need thereof an oral pharmaceutical composition comprisingany of the soft dosage forms described herein.

Another embodiment described herein is a pharmaceutical combinationcomprising any of the compositions described herein and one or moreadditional therapeutic compounds. In one aspect described herein, theone or more additional therapeutic compound comprises one or more ofcimetidine, ranitidine, famotidine, ondansetron, omeprazole,lansoprazole, rabeprazole, esomeprazole, pantoprazole, calciumsupplements, calcium hydroxide, aluminum hydroxide, magnesium hydroxide,or combinations thereof.

Another embodiment described herein is a method for treating fortreating, retarding the progression of, prophylaxis of, delaying theonset of, ameliorating, reducing the symptoms of, or promoting health,including but not limited to of one or more of one or more ofinflammation of the gastrointestinal tract, neoplasia, hyperthyroidism,hypercalcemia, hyperparathyroidism, parathyroid carcinoma, indigestion,heartburn, nausea, flatulence, bloating, acid reflux, irritable bowels,constipation, diarrhea comprising administering to a subject in needthereof the pharmaceutical combination comprising administering to asubject in need thereof any of the oral pharmaceutical combinationsdescribed herein.

Another embodiment described herein is a pharmaceutical dosage form fortreating or alleviating indigestion, heartburn, nausea, flatulence,bloating, acid reflux, diarrhea, or other discomforts of the stomach andgastrointestinal tract, comprising any of the pharmaceuticalcompositions described herein.

Another embodiment described herein is a method for treating oralleviating indigestion, heartburn, nausea, flatulence, bloating, acidreflux, diarrhea, or other discomforts of the stomach andgastrointestinal tract, comprising administering one or more dosageforms comprising any of the pharmaceutical compositions describedherein.

Another embodiment described herein is a means for treating oralleviating indigestion, heartburn, nausea, flatulence, bloating, acidreflux, diarrhea, or other discomforts of the stomach andgastrointestinal tract, comprising administering one or more dosageforms comprising any of the pharmaceutical compositions describedherein.

Another embodiment described herein is a method for manufacturing anoral pharmaceutical composition comprising the steps of: (a) preparing agel fill composition comprising a color solution, a flavor solution anda gel solution wherein: (i) the color solution comprises one or morecolors and excipient in one or more solvents and mixed at a temperaturebetween 30-50° C. until dissolved; (ii) the flavor solution comprisesone or more of plasticizer, menthol and flavor and mixed at atemperature between 30-50° C. until dissolved; (iii) the gel solutioncomprises soaking one or more film forming polymer, plasticizer,sweeteners in one or more solvents, then heated at a temperature between30-70° C. until dissolved; (iv) combining the color solution, flavorsolution, and gel solution and adding bismuth subsalicylate and mixingat a temperature of 20-60° C. until dissolved; (b) preparing a gel masscomposition comprising one or more film forming polymers, one or moreplasticizers, one or more sweeteners, one or more excipients and one ormore solvents; (c) casting the gel composition into films or ribbonsusing heat-controlled drums or surfaces; and (d) forming a soft dosageform comprising a liquid matrix fill using rotary die encapsulationtechnology.

Another embodiment described herein is a soft dosage form comprising anactive pharmaceutical ingredient in a liquid matrix produced by any ofthe methods described herein. In one aspect described herein, the dosageform is stable for at least 1 year at 25° C.

BRIEF DESCRIPTION OF THE DRAWINGS

Further advantageous features of the present disclosure will become moreapparent with the following detailed description when taken withreference to the accompanying drawings, each according to an aspect ofthe present disclosure:

FIG. 1 . Dissolution of a nicotine Liquisoft capsule.

DETAILED DESCRIPTION

Described herein are oral pharmaceutical compositions of comprisingchewable, suckable, or dissolvable soft gel capsules with variousflowable fill compositions.

The oral pharmaceutical compositions described herein are soft gelcapsules, e.g., “LiquiSoft™” capsules, suitable for chewing, sucking, orbuccal dissolution and having pleasing organoleptic propertiescomprising flowable or liquid matrix fills of a variety of activepharmaceutical ingredients, or combinations thereof, and methods forpreparation thereof.

The term “pharmaceutical combination” as used herein refers to either apharmaceutical composition comprising one or more active pharmaceuticalingredient and one or more second therapeutic compounds or apharmaceutical composition comprising an active pharmaceuticalingredient coadministered with a second therapeutic compound.

The phrase “organoleptic properties” as used herein refers to thesensory aspects experienced by one or more subjects, including but notlimited to, sight, smell, taste, mouth feel, moisture content/dryness,plasticity, chewability, dissolution, residue, and aftertaste.

The terms “active ingredient” or “active pharmaceutical ingredient” asused herein refer to a pharmaceutical agent, active ingredient,compound, or substance, compositions, or mixtures thereof, that providea pharmacological, often beneficial, effect.

The terms “dosage” or “dose” as used herein denotes any forms of theactive ingredient formulation that contain an amount sufficient toproduce a therapeutic effect with a single administration. The dosageform described herein is for oral administration. The preferred oraldosage forms described herein are soft gelatin capsules or “soft gels.”

The terms “active pharmaceutical ingredient load” or “drug load” as usedherein refers to the quantity (mass) of the active pharmaceuticalingredient comprised in a single soft capsule fill.

The term “formulation” or “composition” as used herein refers to thedrug in combination with pharmaceutically acceptable excipients. Thisterm includes orally administrable formulations as well as formulationsadministrable by other means.

The term “titration” as used herein refers to the incremental increasein drug dosage to a level that provides the optimal therapeutic effect.

The term “treating” refers to administering a therapy in an amount,manner, or mode effective to improve a condition, symptom, or parameterassociated with a disorder.

The term “conventional dosage from” means a tablet or pill.

The term “prophylaxis” refers to preventing or reducing the progressionof a disorder, either to a statistically significant degree or to adegree detectable to one skilled in the art.

The term “substantially” as used herein means to a great or significantextent, but not completely.

As used herein, all percentages (%) refer to weight percent unless notedotherwise.

The term “about” as used herein refers to any values, including bothintegers and fractional components that are within a variation of up to±10% of the value modified by the term “about.”

As used herein, “a” or “an” means one or more unless otherwisespecified.

Terms such as “include,” “including,” “contain,” “containing” and thelike mean “comprising.”

The term “or” can be conjunctive or disjunctive.

One embodiment described herein, is an oral pharmaceutical compositioncomprising a chewable, suckable, or dissolvable soft capsule shellencapsulating a liquid matrix fill comprising one or more activepharmaceutical ingredients. In one embodiment described herein, thepharmaceutical composition comprises that shown in Table 1.

TABLE 1 Exemplary Liquisoft Composition Exemplary Ingredients % weightCapsule Shell Formulation Polymer(s) 20-60  Plasticizer(s) 30-70 Polymer Modifier(s) 0-2  Sweetener(s) 0-50 Solvent(s) 10-40  Excipients:flavorings, 0.1-10  colorings, opacifiers, etc. TOTAL 100% Matrix FillFormulation Hydrophilic Vehicle(s) 20-90  Flavoring(s) 0-10 Sweetener(s)0-50 Optional Excipient(s) 0-25 Solvent(s) 0-25 Active Pharmaceutical0-60 Ingredient(s) (APIs) TOTAL 100%

One embodiment described herein is an oral pharmaceutical compositionsuitable for chewing, sucking, or buccal dissolution. In one embodiment,the composition comprises a gel mass suitable for forming soft gelcapsules. In another embodiment, the composition comprises a liquidmatrix fill. In one embodiment, the composition comprises a flowable gelmatrix fill. In another embodiment, the composition comprises a viscoussemi-solid matrix fill. In another embodiment, the composition comprisesa soft gel capsule and a liquid matrix fill. In one embodiment, thepharmaceutical composition provides a “burst” of sweetened flavoredliquid comprising one or more active pharmaceutical ingredients to theoral cavity when a subject manipulates the dosage form within the mouth.The subject may bite or chew the dosage form, suck the dosage form, orallow the dosage form to slowly dissolve in the oral cavity. Uponrupturing the gel capsule shell by chewing, sucking, or dissolutionwithin the mouth, the liquid matrix is released and provides a burst ofliquid sensation to the subject's oral cavity. The sensation may besweet, flavored, cooling, or a combination thereof. One or more of these“sensations” can be used to mask poor tasting active pharmaceuticalingredients or provide soothing sensations to a subject's oral mucosa,sinuses, or throat, for example.

One embodiment described herein is a soft capsule shell comprising oneor more film-forming polymers, one or more plasticizers, one or morepolymer modifiers, one or more solvents, one or more sweeteners, andoptionally, one or more pharmaceutically acceptable excipients,including but not limited to coloring agents, flavorings, opacifiers,hygroscopic polymers, thickening agents, surfactants or the like.

Chewable soft capsule shells are described in U.S. Pat. Nos. 6,258,380;8,097,279; 8,241,665; 8,414,916; and 8,765,174, each of which is inincorporated by reference herein for such teachings.

Another embodiment described herein is a matrix fill comprising one ormore hydrophilic vehicles, one or more sweeteners, one or moreflavorings, one or more solvents, optionally, one or more excipients,and one or more active pharmaceutical ingredients. In one embodimentdescribed herein, the composition comprises that shown in Table 2.

TABLE 2 Exemplary Liquisoft Composition Weight Percentage ComponentExemplary Component (%) Capsule Shell Formulation Polymers Gelatin, 150Bloom 10-40 Gelatin, 100 Bloom  1-20 Gelatin Hydrolysate 0-7 HydrolyzedCollagen 0-7 Plasticizer(s) Glycerol 10-50 Maltitol (Lycasin ®)  1-30Xylitol  0-20 Sweeteners Sucralose 0-5 Polymer Citrate 0-2 ModifierSolvent Water 10-40 TOTAL 100% Matrix Fill Formulation HydrophilicPropylene Glycol  0-20 Vehicle Polyethylene Glycol 400 10-50Polyvinylpyrrolidone K30 0-2 Flavors Citric Acid 0-3 Lactic Acid 0-3Sodium Citrate 0-3 Sweeteners Maltitol (Lycasin ®) 20-70 Mannitol 0-5Sucralose 0-2 Thaumatin (Talin ®) 0-5 Glycyrrhizic acid salts 0-5(MagnaSweet ®) Excipients  0-25 Solvent Water  0-15 Active e.g.,Dextromethorphan  0-15 Pharmaceutical Hydrobromide Ingredients (API)TOTAL 100%

In one embodiment described herein, the soft capsule shell comprises oneor more film-forming polymers. In one embodiment, the polymer comprisesgelatin having a Bloom strength of about 50 to about 400 Bloom,hydrolyzed gelatin, gelatin hydrolysate, hydrolyzed collagen, sodium andcalcium alginate; natural and modified starch and starch hydrolysates,pectins and amylopectins, cellulose derivatives, such as orhydroxypropylmethylcellulose (HPMC), methylcellulose, cellulose, orcombinations thereof. In one aspect described herein, the polymercomprises one or more gelatins or gelatin hydrolysates.

Examples of gelatin compositions that are useful for the pharmaceuticalcompositions described herein comprise acid bone gelatin, pig skingelatin, chicken skin gelatin, fish gelatin, acid hide gelatin, gelatinhydrolysate, lime bone gelatin, or combinations thereof. Gelatins can beclassified as either Type A or Type B gelatin. Type A gelatin is derivedfrom the acid hydrolysis of collagen (e.g., acid bone gelatin or pigskin gelatin), while Type B gelatin (e.g., lime bone gelatin) is derivedfrom the alkaline hydrolysis of collagen. Traditionally, bovine bonesand skins are used as raw materials for manufacturing Type A and Type Bgelatin, while porcine skins are used extensively for manufacturing TypeA gelatin. In addition, at neutral pH values, Type A gelatins (acidprocessed gelatins) are typically net cationic (e.g., isoelectric pointof about 7-9) and Type B gelatins (alkali processed gelatins) aretypically net anionic (e.g., isoelectric point of about 4.5-5.3). Type Agelatin typically has higher plasticity and elasticity than type Bgelatin; type B gelatin typically has higher gel strength than type Agelatin.

The strength of gelatin compositions is typically defined by their Bloomstrength or grade. The Bloom test determines the weight (in grams)needed by a 0.5-inch diameter probe to deflect the surface of a gel 4 mmwithout breaking it. The result is expressed as “Bloom” or “Bloomstrength.” The pharmaceutical compositions described herein utilizegelatins with Bloom strengths in the range of about 50 Bloom to about400 Bloom, including each integer within the specified range. In oneembodiment, Bloom strengths for pharmaceutical compositions describedherein are about 50 Bloom to about 250 Bloom including each integerwithin the specified range. In some embodiments, the gelatin Bloomstrength is about 50 Bloom, about 80 Bloom, about 100 Bloom, about 120Bloom, about 150 Bloom, about 180 Bloom, about 200 Bloom, or about 250Bloom. In one embodiment, the gelatin Bloom strength is 100 Bloom. Inanother embodiment, the gelatin Bloom strength is 150 Bloom. In anotherembodiment, the gelatin Bloom strength is 195 Bloom. In anotherembodiment, the gelatin Bloom strength is 200 Bloom. In another aspect,the one or more film-forming polymers comprise one or more of gelatin,partially hydrolyzed gelatin, hydrolyzed gelatin, or combinationsthereof.

In one embodiment described herein, the one or more polymers compriseone or more gelatins having a Bloom of about 100. In another aspect, theone or more polymers comprise one or more gelatins having a Bloom ofabout 150. In another aspect, the one or more polymers comprise one ormore of partially hydrolyzed gelatin, hydrolyzed gelatin, hydrolyzedcollagen, or combinations thereof.

In another embodiment described herein, the soft capsule shell comprisesone or more plasticizers. As used herein, a plasticizer is a substance,often a polyol, that provides flexibility and softens the capsule. Inone embodiment, the plasticizer comprises one or more of glycerol,sorbitol, mannitol, maltitol (Lycasin®), xylitol (Xylisorb®), orcombinations thereof. In one aspect, the plasticizer comprises glycerol,sorbitol, or combinations thereof. In one aspect, the plasticizercomprises glycerol, maltitol (Lycasin®), xylitol, or combinationsthereof.

In another embodiment described herein, the soft capsule shell comprisesone or more sweeteners. In one embodiment, the sweetener comprises oneor more of sucralose, xylitol, aspartame, acesulfame potassium,acesulfame salts, steviol glycosides (e.g., Stevia®, Truvía®), thaumatin(e.g., Talin®), glycyrrhizic acid salts (MagnaSweet®), or combinationsthereof. In one aspect, the sweetener comprises sucralose.

In another embodiment described herein, the soft capsule shell comprisesone or more polymer modifiers. In one embodiment, the polymer modifiercomprises an organic acid. In another embodiment, the polymer modifierscomprise one or more of citric acid, acetic acid, lactic acid, malicacid, tartaric acid, glutamic acid, aspartic acid, malic acid, succinicacid, fumaric acid, or combinations thereof. In one aspect, the polymermodifier comprises citric acid.

In another embodiment, the soft capsule shell comprises one or moresolvents. In one aspect, the solvent comprises water.

In one embodiment, the one or more polymer comprises a weight percentageof about 20% to about 60% by weight of the shell, including each integerwithin the specified range. In another embodiment, the one or morepolymers comprise about 20% to about 50%, about 25% to about 55%, orabout 30% to about 45% by weight of the shell. In one aspect, the totalpolymer comprises about 20%, about 25%, about 30%, about 35%, about 40%,about 45%, about 50%, about 55%, or about 60% by weight of the shell. Inanother aspect, the total one or more polymers comprise about 32% byweight of the shell. In another aspect, the total one or more polymerscomprise about 30%, about 31%, about 33%, 34%, or about 37% by weight ofthe shell.

In another embodiment, the one or more polymers comprise gelatin havinga Bloom of about 150 and a weight percentage of about 10% to about 40%by weight of the shell, including each integer within the specifiedrange. In one embodiment, gelatin having a Bloom of about 150 comprisesabout 10% to about 30%, about 15% to about 30%, about 15% to about 25%,or about 15% to about 20% by weight of the shell. In one aspect, gelatinhaving a Bloom of about 150 comprises about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, or about 40% by weight of the shell. Inanother aspect, gelatin having a Bloom of about 150 comprises about 19%by weight of the shell. In another aspect, gelatin having a Bloom ofabout 150 comprises about 14%, about 16%, about 18%, about 20%, or about22% by weight of the shell.

In another embodiment, the one or more polymers comprise a gelatinhaving a Bloom of about 100 and a weight percentage of about 1% to about30% by weight of the shell, including each integer within the specifiedrange. In another embodiment, gelatin having a Bloom of about 100comprises about 1% to about 20%, 1% to about 15%, about 1% to about 10%,or about 5% to about 10% by weight of the shell. In one aspect, gelatinhaving a Bloom of about 100 comprises about 1%, about 5%, about 10%,about 15%, about 20%, about 25% or about 30% by weight of the shell. Inanother aspect, gelatin having a Bloom of about 100 comprises 8% byweight of the shell. In another aspect, gelatin having a Bloom of about100 comprises about 5%, about 7%, about 10%, 15%, 18%, or about 28% byweight of the shell.

In another embodiment, the one or more polymers comprise gelatinhydrolysate having a weight percentage of about 0 to about 7% by weightof the shell, including each integer within the specified range. In oneembodiment, gelatin hydrolysate comprises about 0.25% to about 6.75%,about 0.50% to about 6.50%, about 1% to about 6%, or about 1.5% to about5.5% by weight of the shell. In one aspect, gelatin hydrolysatecomprises about 0%, about 2%, about 4%, or about 7% by weight of theshell. In another aspect, the gelatin hydrolysate comprises about 5% byweight of the shell. In another aspect, the gelatin hydrolysatecomprises about 2%, about 4%, about 4.5%, about 5.5%, or about 6% byweight of the shell.

In another embodiment, the one or more polymers comprise hydrolyzedcollagen at a weight percentage of about 0% to about 7% by weight of theshell, including each integer within the specified range. In oneembodiment, hydrolyzed collagen comprises about 0.25% to about 6.75%,about 0.50% to about 6.50%, about 1% to about 6%, or about 1.5% to about5.5% by weight of the shell. In one aspect, hydrolyzed collagencomprises about 0%, about 2%, about 4%, or about 7% by weight of theshell. In another aspect, hydrolyzed collagen comprises about 5% byweight of the shell. In another aspect, hydrolyzed collagen comprisesabout 4%, about 4.5%, about 5%, about 5.5%, or about 6% by weight of theshell.

In another embodiment, one or more plasticizers comprise a weightpercentage of about 30% to about 70% by weight of the shell, includingeach integer within the specified range. In one embodiment, the one ormore plasticizers comprise about 30% to about 60%, about 30% to about50%, or about 35% to about 45% by weight of the shell. In one aspect,one or more plasticizers comprise about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, or about 70% by weightof the shell. In another aspect, the total plasticizer comprises about43% by weight of the shell. In another aspect, the total plasticizercomprises about 36%, about 39%, about 40%, about 41%, about 42%, about44%, or about 45% by weight of the shell.

In another embodiment, the one or more plasticizers comprise glycerol,xylitol, maltitol, or a combination thereof and comprise a weightpercentage of about 10% to about 50% by weight of the shell, includingeach integer within the specified range. In another embodiment, glycerolcomprises about 10% to about 40%, about 15% to about 35%, about 15% toabout 30%, or about 20% to about 25% by weight of the shell. In oneaspect, glycerol comprises about 10%, about 15%, about 20%, about 25%,about 30%, about 35%, about 40%, about 45%, or about 50% by weight ofthe shell. In another aspect, glycerol comprises about 24% by weight ofthe shell. In another aspect, glycerol comprises about 19%, about 20%,about 21%, about 22%, about 23%, about 24%, or about 25% by weight ofthe shell.

In another embodiment, the one or more plasticizers comprise xylitolhaving a weight percentage of 0% to about 20% by weight of the shell,including each integer within the specified range. In one embodiment,xylitol comprises about 1% to about 15%, about 1% to about 10%, or about1% to about 5% by weight of the shell. In one aspect, xylitol comprisesabout 0%, about 5%, about 10%, about 15%, or about 20% by weight of theshell. In another aspect, xylitol comprises about 3% by weight of theshell. In another aspect, xylitol comprises about 0.5%, about 1%, about4%, or about 5% by weight of the shell.

In another embodiment, the one or more plasticizers comprise maltitolhaving a weight percentage of about 1% to about 30% by weight of theshell, including each integer within the specified range. In oneembodiment, maltitol comprises about 1% to about 30%, about 5% to about25%, about 10% to about 25%, or about 15% to about 20% by weight of theshell. In one aspect, maltitol comprises about 1%, about 5%, about 10%,about 15%, about 20%, about 25%, or about 30% by weight of the shell. Inanother aspect, maltitol comprises about 17% by weight of the shell. Inanother aspect, maltitol comprises about 15%, about 16%, or about 18% byweight of the shell.

In another embodiment, the one or more polymer modifiers comprise about0.01% to about 2% by weight of the shell, including each integer withinthe specified range. In one embodiment, the one or more polymermodifiers comprise about 0.25% to about 1.5%, about 0.25% to about 1%,or about 0.25% to about 0.75% by weight of the shell. In one aspect, thepolymer modifier comprises about 0%, about 0.25%, about 0.50%, about0.75%, about 1%, about 1.25%, about 1.50%, about 1.75%, or about 2.0% byweight of the shell. In another aspect, the polymer modifier comprisesabout 0.5% by weight of the shell. In another aspect, the polymermodifier comprises about 0.25%, about 0.3%, or about 0.6% by weight ofthe shell.

In another embodiment, the polymer modifier comprises citrate having aweight percentage of about 0.01% to about 2% by weight of the shell,including each integer within the specified range. In anotherembodiment, citrate comprises about 0.25% to about 1.5%, about 0.25% toabout 1%, or about 0.25% or about 0.75% by weight of the shell. In oneaspect, citrate comprises about 0%, about 0.25%, about 0.50%, about0.75%, about 1%, about 1.25%, about 1.50%, about 1.75%, or about 2.0% byweight of the shell. In another aspect, citrate comprises about 0.5% byweight of the shell. In another aspect, citrate comprises about 0.25%,about 0.3%, or about 0.6% by weight of the shell.

In another embodiment, the one or more sweeteners comprise sucralosehaving a weight percentage of about 0.01% to about 5% by weight of theshell, including each integer within the specified range. In oneembodiment, sucralose comprises about 0.1% to about 0.9%, about 0.1% toabout 0.75%, or about 0.1% to about 0.5% by weight of the shell. In oneaspect, sucralose comprises about 0%; about 0.25%, about 0.50%, about0.75%, or about 1% by weight of the shell. In another aspect, sucralosecomprises about 0.2%. In another aspect, sucralose comprises about 0.1%,about 0.15%, about 0.25%, or about 0.3% by weight of the shell.

In another embodiment, the one or more sweeteners comprise xylitolhaving a weight percentage of about 0.01% to about 5% by weight of theshell, including each integer within the specified range. In oneembodiment, xylitol comprises about 0.1% to about 4%, about 0.1% toabout 3%, or about 0.5% to about 2.5% by weight of the shell. In oneaspect, xylitol comprises about 0%; about 0.25%, about 0.50%, about0.75%, about 1%, about 1.5%, about 2%, or about 2.5% by weight of theshell. In another aspect, xylitol comprises about 2.5%. In anotheraspect, xylitol comprises about 1.5%, about 2%, about 2.25%, or about2.75% by weight of the shell.

In another embodiment, one or more solvents comprise about 10% to about40% by weight of the shell, including each integer within the specifiedrange. In another embodiment, the solvents comprise about 10% to about35%, about 15% to about 30%, or about 20% to about 30% by weight of theshell. In another aspect, the solvents comprise about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, or about 40% by weight ofthe shell. In another aspect, the solvents comprise 23% by weight of theshell. In another aspect, the solvents comprise about 17%, about 20%,about 25%, or about 30% by weight of the shell.

In another embodiment, the solvent comprises water having a weightpercentage of about 10% to about 40% by weight of the shell, includingeach integer within the specified range. In another embodiment, watercomprises about 10% to about 35%, about 15% to about 30%, or about 20%or about 30% by weight of the shell. In another aspect, water comprisesabout 10%; about 15%, about 20%, about 25%, about 30%, about 35%, orabout 40% by weight of the shell. In another aspect, water comprises 23%by weight of the shell. In another aspect, water comprises about 17%,about 20%, about 25%, or about 30% by weight of the shell.

In another embodiment, the ratio of total polymer to total plasticizerin the shell comprises about 1:1 to about 1:2, including each ratiowithin the specified range. In another embodiment, the ratio of totalpolymer to total plasticizer in the shell is about 1:1 to about 1:1.8,about 1:1 to about 1:1.6, about 1:1 to about 1:4. In one aspect, theratio of total polymer to total plasticizer in the shell is about 1:1.1,about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about1:1.7, about 1:1.8, about 1:1.9, or about 1:2. In another aspect, theratio of total polymer to total plasticizer in the shell is about 1:1.3.In another aspect, the ratio of total polymer to total modifier in theshell is about 1:0.75, about 1:1.25, about 1:1.5, or about 1:1.75.

In another embodiment, the ratio of total polymer to total polymermodifier in the shell comprises about 1:0.01 to about 1:0.1, includingeach ratio within the specified range. In one embodiment, the ratio oftotal polymer to total polymer modifier in the shell is about 1:0.01 toabout 1:0.08, about 1:0.01 to about 1:0.06, or about 1:0.01 to about1.04. In one aspect, the ratio of total polymer to total plasticizer inthe shell is about 1:0.01, about 1:0.02, about 1:0.03, about 1:0.04,about 1:0.05, about 1:0.06, about 1:0.07, about 1:0.08, about 1:0.09, orabout 1:1. In another aspect, the ratio of total polymer to totalpolymer modifier in the shell is about 1:0.02. In another aspect, theratio of total polymer to total modifier in the shell is about 1:0.01,or about 1:0.03.

In one embodiment, soft capsules are made using a rotary die apparatusas described in U.S. Pat. Nos. 5,459,983; 5,146,730; and 6,482,516, eachof which are incorporated by reference herein for such teachings.

Another embodiment described herein includes a process of manufacturingsoft capsules comprising the pharmaceutical compositions as describedherein. The process includes preparing a gel mass composition comprisingone or more polymers, one or more plasticizers, one or more polymermodifiers, one or more solvents, and appropriate flavorings, sweeteners,coloring agents, or other excipients; casting the gel mass into films orribbons using heat-controlled drums or surfaces; and manufacturing asoft capsule comprising a matrix fill using rotary die technology. Thethickness of the films or ribbons that form the soft capsule shell isfrom about 0.010 inches (≈0.254 mm) to about 0.050 inches (≈1.27 mm),including all integers within the specified range. The shell thicknesscan be about 0.010 inch (≈0.254 mm), about 0.015 inch (≈0.381 mm), about0.02 in (≈0.508 mm), about 0.03 in (≈0.762 mm), about 0.04 in (≈1.02mm), or about 0.05 in (≈1.27 mm). In one embodiment, the thickness isabout 0.02 inches (≈0.508 mm) to about 0.040 inches (≈1.02 mm). In oneembodiment, the shell thickness is about 0.028 inches (≈0.711 mm). Inanother embodiment, the shell thickness is about 0.033 inches (≈0.838mm). In another embodiment, the shell thickness is about 0.038 inches(≈0.965 mm).

In one embodiment described herein, the soft capsule shell describedherein, encapsulates a matrix fill as described herein. In anotherembodiment described herein, the soft capsule shell and encapsulatedmatrix fill comprises an outer dimension from about 2 oval to about 30oval including all iterations of capsule size within the specified range(e.g., 2 oval, 3 oval, 4 oval, 5 oval, 6 oval, 7 oval, 8 oval, 10 oval,12 oval, 16 oval, 20, or 30 oval). In another embodiment describedherein, the soft capsule shell and encapsulated matrix fill comprises anouter dimension from about 2 round to about 28 round including alliterations of capsule size within the specified range (e.g., 2 round, 3round, 4 round, 5 round, 6 round, 7 round, 8 round, 10 round, 12 round,16 round, 20 round or 28 round). In another embodiment described herein,the soft capsule shell and encapsulated matrix fill comprises an outerdimension from about 2 oblong to about 22 oblong including alliterations of capsule size within the specified range (e.g., 2 oblong, 3oblong, 4 oblong, 5 oblong, 6 oblong, 7 oblong, 8 oblong, 10 oblong, 11,oblong, 12 oblong, 14 oblong, 16 oblong, 20 oblong, or 22 oblong).Dimension specifications of soft capsules and tablets are known to thoseskilled in the art. See Remington's Essentials of Pharmaceutics,Pharmaceutical Press Publishing Company, London, UK, 1^(st) Edition,2013, which is incorporated by reference herein for such teachings.

In one embodiment, the hydrophilic vehicle may be anhydrous andcompatible with soft gelatin capsules. Non-limiting exemplary vehiclescomprise Capmul® MCM, Captex® 355, Cremophor® RH 40, Croscarmellose,Crospovidone, Crospovidone CL, Crospovidone CL-F, Crospovidone CL-M,Imwitor® 742, Kollidon® CL, Kollidon® CL-F, Kollidon® CL-M, Labrafac™Lipophile WL 1349, Labrafil® M2125CS, Labrasol®, Lutrol® F 68, Maisine™35-1, mannitol, Miglyol® 812, Pearlitol® Flash, Peceol®, Plurol® OleiqueCC 497, Povidone K 17, Povidone K 30, polyethylene glycol 200,polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol800, polyethylene glycol 1000, polyethylene glycol 2000, polyethyleneglycol 3350, propylene glycol, glycerol, Lycasin 80/55, sorbitolspecial, xylitol, maltitol or mixtures thereof. In on embodiment thehydrophilic vehicle comprises one or more hydro-alcohols includingpolyethylene glycols of a molecular weight ranging from about 200 toabout 8000, or a mixture or combination thereof.

In another embodiment, the hydrophilic vehicle may comprise ahygroscopic polymer. In one embodiment, the hygroscopic polymers includepolyvinylpyrrolidone, copovidone, hydroxypropylmethylcellulose,hydroxypropylcellulose, ethyl cellulose, methylcellulose, andpolyethylene oxide. Suitable hygroscopic polymers include polyvinylalcohol, a copolymer of polyvinylpyrrolidone and polyvinyl acetate,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, such asPOLYOX™ 100,000-600,000 MW, acacia, dextrin, cyclodextrins, starch, polyhydroxyethylmethacrylate, a water-soluble non-ionic polymethacrylate orcopolymer thereof, a modified cellulose, a modified polysaccharide, anon-ionic gum, or a non-ionic polysaccharide.

In another embodiment, the hydrophilic vehicle may comprise one or morelipids or lipophilic vehicles. In one aspect, the lipid or lipophilicvehicle may be a liquid or a solid or a semisolid lipid or lipophilicvehicle. Suitable non-limiting liquid lipid or lipophilic vehiclescomprise olive oil, soybean oil, sunflower oil, canola oil, palmitoleicacid, oleic acid, myristoleic acid, linoleic acid, arachidonic acid,paraffin oil, mineral oil, or a mixture or combination thereof. Thelipid or lipophilic vehicle can be a semi-solid lipophilic vehicle suchas a polyethylene glycol glyceride ester, e.g., Gelucire® 33/01,Gelucire® 37/02, Gelucire® 39/01, Gelucire® 43/01, Gelucire® 44/14,Gelucire® 50/02, Gelucire® 50/13, Gelucire® 53/10, or Gelucire® 62/02; aparaffin wax, carnauba wax, or bee's wax.

In another embodiment, the hydrophilic vehicle may comprise releaseregulators such as fatty acid salts, fatty acid esters, or fatty acidpolyoxyethylene derivatives. The release regulator can also be asurfactant having a hydrophilic/lipophilic balance (HLB) value betweenabout 2 and about 40. The HLB characteristic of surfactants can bedetermined in accordance with “Physical Pharmacy: Physical ChemicalPrinciples in the Pharmaceutical Sciences,” Fourth Edition, pp. 371-373,A. Martin, Ed., Lippincott Williams & Wilkins, Philadelphia (1993),which is incorporated by reference herein for such teachings.

In another embodiment, the hydrophilic vehicle may comprise emulsifyingor solubilizing agents such as acacia, cholesterol, diethanolamine,glyceryl monostearate, lanolin alcohols, lecithin, mono- anddi-glycerides, monoethanolamines, oleic acids, oleyl alcohols,poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 80, propylene glycol diacetate, propyleneglycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, stearic acid, simethicone, trolamine, emulsifying wax, orcombinations thereof.

In one embodiment described herein, the matrix fill comprises one ormore hydrophilic vehicles. In another aspect, the one or morehydrophilic vehicles comprise propylene glycol, polyethylene glycol 400,polyvinylpyrrolidone K30, or combinations thereof.

In another embodiment described herein, the matrix fill comprises one ormore flavorings. In one embodiment, the one or more flavorings comprisecitric acid, lactic acid, sodium citrate, anethole, benzaldehyde, ethylvanillin, Eucalyptol, glycine, menthol, methyl salicylate, monosodiumglutamate, orange flower oil, peppermint, peppermint oil, peppermintspirit, rose oil, stronger rose water, thymol, tolu balsam tincture,vanilla, vanilla tincture, vanillin or combinations thereof. In oneaspect, the flavorings comprise one or more of citric acid, acetic acid,lactic acid, malic acid, tartaric acid, or combinations thereof. Inanother aspect, the flavorings comprise citric acid, lactic acid, orcombinations thereof.

In another embodiment, the matrix fill comprises at least one or moresweeteners. In one embodiment, the one or more sweeteners comprisemannitol, thaumatin, glycyrrhizic acid salt, maltitol, sucralose,acesulfame salts, steviol glycosides (e.g., Stevia®, Truvía®),saccharin, calcium saccharin, sodium saccharin, aspartame, acesulfamepotassium, agave nectar, high-fructose corn syrup, honey, dextrates,dextrose, excipient dextrose and simple sugars such as glucose,fructose, sucrose, sucralose, lactose, or combinations thereof. In oneaspect, the sweeteners comprise one or more of mannitol, maltitol (e.g.,Lycasin®), xylitol, sucralose, thaumatin (e.g., Talin®), glycyrrhizicacid salts (MagnaSweet®), or combinations thereof.

In another embodiment the matrix fill comprises at least one solvent. Inone aspect, the solvent is water.

Additional pharmaceutical excipients useful for capsule shells or matrixfills as described herein include, for example, the following:Acidifying agents (acetic acid, glacial acetic acid, citric acid,fumaric acid, hydrochloric acid, diluted hydrochloric acid, malic acid,nitric acid, phosphoric acid, diluted phosphoric acid, sulfuric acid,tartaric acid); Alkalizing agents (ammonia solution, ammonium carbonate,diethanolamine, diisopropanolamine, potassium hydroxide, sodiumbicarbonate, sodium borate, sodium carbonate, sodium hydroxide,trolamine); Antifoaming agents (dimethicone, simethicone); Antimicrobialpreservatives (benzalkonium chloride, benzalkonium chloride solution,benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben,cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol,dehydroacetic acid, ethylparaben, methylparaben, methylparaben sodium,phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuricnitrate, potassium benzoate, potassium sorbate, propylparaben,propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodiumpropionate, sorbic acid, thimerosal, thymol); Antioxidants (ascorbicacid, ascorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate,sodium formaldehyde sulfoxylate, sodium metabisulfite, sodiumthiosulfate, sulfur dioxide, tocopherol, tocopherols excipient);Buffering agents (acetic acid, ammonium carbonate, ammonium phosphate,boric acid, citric acid, lactic acid, phosphoric acid, potassiumcitrate, potassium metaphosphate, potassium phosphate monobasic, sodiumacetate, sodium citrate, sodium lactate solution, dibasic sodiumphosphate, monobasic sodium phosphate); Chelating agents (edetatedisodium, ethylenediaminetetraacetic acid and salts, edetic acid);Coating agents (sodium carboxymethylcellulose, cellulose acetate,cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceuticalglaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer,methylcellulose, polyvinyl acetate phthalate, shellac, sucrose, titaniumdioxide, carnauba wax, microcrystalline wax, zein); Colorants (caramel,red, yellow, black or blends, ferric oxide); Complexing agents(ethylenediaminetetraacetic acid and salts (EDTA), edetic acid, gentisicacid ethanolamide, oxyquinoline sulfate); Desiccants (calcium chloride,calcium sulfate, silicon dioxide); Emulsifying and/or solubilizingagents (acacia, cholesterol, diethanolamine (adjunct), glycerylmonostearate, lanolin alcohols, mono- and di-glycerides,monoethanolamine (adjunct), lecithin, oleic acid (adjunct), oleylalcohol (stabilizer), poloxamer, polyoxyethylene 50 stearate, polyoxyl35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleylether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate20, polysorbate 40, polysorbate 60, polysorbate 80, diacetate,monostearate, sodium lauryl sulfate, sodium stearate, sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, stearic acid, trolamine, emulsifying wax); Filtering aids(powdered cellulose, purified siliceous earth); Flavors and perfumes(anethole, benzaldehyde, ethyl vanillin, menthol, methyl salicylate,monosodium glutamate, orange flower oil, peppermint, peppermint oil,peppermint spirit, rose oil, stronger rose water, thymol, tolu balsamtincture, vanilla, vanilla tincture, vanillin); Humectants (glycerol,hexylene glycol, sorbitol); Plasticizers (e.g., castor oil, diacetylatedmonoglycerides, diethyl phthalate, glycerol, mono- and di-acetylatedmonoglycerides, propylene glycol, triacetin, triethyl citrate); Polymers(e.g., cellulose acetate, alkyl celluloses, hydroxyalkyl, acrylicpolymers and copolymers); Solvents (acetone, alcohol, diluted alcohol,amylene hydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride,chloroform, corn oil, cottonseed oil, ethyl acetate, glycerol, hexyleneglycol, isopropyl alcohol, methyl alcohol, methylene chloride, methylisobutyl ketone, mineral oil, peanut oil, propylene carbonate, sesameoil, water for injection, sterile water for injection, sterile water forirrigation, purified water); Sorbents (powdered cellulose, charcoal,purified siliceous earth); Carbon dioxide sorbents (barium hydroxidelime, soda lime); Stiffening agents (hydrogenated castor oil,cetostearyl alcohol, cetyl alcohol, cetyl esters wax, hard fat,paraffin, polyethylene excipient, stearyl alcohol, emulsifying wax,white wax, yellow wax); Suspending and/or viscosity-increasing agents(acacia, agar, alginic acid, aluminum monostearate, bentonite, purifiedbentonite, magma bentonite, carbomer, carboxymethylcellulose calcium,carboxymethylcellulose sodium, carboxymethylcellulose sodium 12,carrageenan, microcrystalline and carboxymethylcellulose sodiumcellulose, dextrin, gelatin, guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesiumaluminum silicate, methylcellulose, pectin, polyethylene oxide,polyvinyl alcohol, povidone, alginate, silicon dioxide, colloidalsilicon dioxide, sodium alginate, tragacanth, xanthan gum); Sweeteningagents (aspartame, dextrates, dextrose, excipient dextrose, fructose,mannitol, saccharin, calcium saccharin, sodium saccharin, sorbitol,solution sorbitol, sucrose, compressible sugar, confectioner's sugar,syrup); Surfactants (simethicone); Tablet binders (acacia, alginic acid,sodium carboxymethylcellulose, microcrystalline cellulose, dextrin,ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, povidone,pregelatinized starch, syrup); Tablet and/or capsule diluents (calciumcarbonate, dibasic calcium phosphate, tribasic calcium phosphate,calcium sulfate, microcrystalline cellulose, powdered cellulose,dextrates, dextrin, dextrose excipient, fructose, kaolin, lactose,mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressiblesugar, confectioner's sugar); Tablet disintegrants (alginic acid,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, starch, pregelatinizedstarch); Tablet and/or capsule lubricants (calcium stearate, glycerylbehenate, magnesium stearate, light mineral oil, sodium stearylfumarate, stearic acid, purified stearic acid, talc, hydrogenatedvegetable oil, zinc stearate); Thickening agents (gelatin having a Bloomstrength of 50-100); Tonicity agent (dextrose, glycerol, mannitol,potassium chloride, sodium chloride); Vehicle: flavored and/or sweetened(aromatic elixir, compound benzaldehyde elixir, iso-alcoholic elixir,peppermint water, sorbitol solution, syrup, tolu balsam syrup); Vehicle:oleaginous (almond oil, corn oil, cottonseed oil, ethyl oleate,isopropyl myristate, isopropyl palmitate, mineral oil, light mineraloil, myristyl alcohol, octyl dodecanol, olive oil, peanut oil, persicoil, sesame oil, soybean oil, squalane); Vehicle: solid carrier (sugarspheres); Vehicle: sterile (Bacteriostatic water for injection,bacteriostatic sodium chloride injection); Viscosity-increasing (seesuspending agent); Water repelling agent (cyclomethicone, dimethicone,simethicone); and/or solubilizing agent (benzalkonium chloride,benzethonium chloride, cetylpyridinium chloride, docusate sodium,nonoxynol 9, nonoxynol 10, octoxynol 9, poloxamer, polyoxyl 35 castoroil, polyoxyl 40, hydrogenated castor oil, polyoxyl 50 stearate,polyoxyl 10 oleyl ether, polyoxyl 20, cetostearyl ether, polyoxyl 40stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate80, sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate,sorbitan monopalmitate, sorbitan monostearate, tyloxapol). This list isnot meant to be exclusive, but instead merely representative of theclasses of excipients and the particular excipients that may be used inoral dosage forms as described herein.

In one embodiment, one or more hydrophilic vehicles comprise about 20%to about 95% by weight of the matrix fill, including each integer withinthe specified range. In another embodiment, the one or more hydrophilicvehicles comprise about 20% to about 50%, about 25% to about 50%, about30% or about 45%, about 40% to about 60%, or about 50% to about 95% byweight of the matrix fill. In one aspect, the total hydrophilic vehiclecomprises about 20%, about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, or about 90% by weight of the matrix fill. Inanother aspect, the total hydrophilic vehicle comprises about 40%, about60%, about or about 90% by weight of the matrix fill.

In another embodiment, the hydrophilic vehicle comprises polypropyleneglycol having a weight percentage of about 0% to about 20% by weight ofthe matrix fill, including each integer within the specified range. Inone embodiment, the polypropylene glycol comprises about 0% to about15%, about 0% to about 10%, or about 5% to about 10% by weight of thematrix fill. In one aspect, the polypropylene glycol comprises about 0%,about 5%, about 10%, about 15%, or about 20% by weight of the matrixfill. In another aspect, polypropylene glycol comprises about 8% byweight of the shell. In another aspect, the polypropylene glycolcomprises about 2%, about 6%, about 7%, or about 9% by weight of thefill.

In another embodiment, the hydrophilic vehicle comprises polyethyleneglycol 400 having a weight percentage of about 0.01% to about 50% byweight of the matrix fill, including each integer within the specifiedrange. In one embodiment, polyethylene glycol 400 comprises about 0.01%to about 40%, about 0.1% to about 30%, or about 10% to about 30% byweight of the matrix fill. In one aspect, polyethylene glycol 400comprises about 1%, about 10%, about 15%, about 20%, about 25%, about30%, about 40%, about 45%, or about 50% by weight of the matrix fill. Inanother aspect, polyethylene glycol 400 comprises about 20% by weight ofthe fill. In another aspect, polyethylene glycol 400 is about 1%, about16%, about 18%, about 20%, about 25%, about 30%, about 45%, or about 50%by weight of the fill.

In another embodiment, the hydrophilic vehicle comprisespolyvinylpyrrolidone K30 having a weight percentage of about 0% to about2% by weight of the matrix fill, including each integer within thespecified range. In one embodiment, polyvinylpyrrolidone K30 comprisesabout 0.25% to about 1.75%, about 0.50% to about 1.75%, or about 0.75%to about 1.75% by weight of the matrix fill. In one aspect,polyvinylpyrrolidone K30 comprises about 0%, about 0.25%, about 0.50%,about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2%by weight of the matrix fill. In another aspect, polyvinylpyrrolidoneK30 comprises about 1.2% by weight of the fill. In another aspect,polyvinylpyrrolidone K30 comprises about 1%, about 1.1%, about 1.3%,about 1.4%, about 1.5%, or about 1.7% by weight of the fill.

In another embodiment, one or more excipients comprise about 0.1% toabout 25% by weight of the matrix fill, including each integer withinthe specified range. In one embodiment, the one or more excipientscomprise about 0.1% to about 10%, about 10% to about 25%, or about 5% toabout 15% by weight of matrix fill. In one aspect, the one or moreexcipients comprise about 0.1%, 1%, about 5%, about 10%, about 15%,about 20%, or about 25%, by weight of the matrix fill. In one aspect,the one or more excipients comprise about 10% by weight of the fill. Inanother aspect, the one or more excipients comprise about 1%, about 2%,about 2.5%, about 3%, about 4%, about 5%, about 10%, about 15%, or about20% by weight of the fill.

In another embodiment, one or more sweeteners comprise about 0.1% toabout 20% by weight of the matrix fill, including each integer withinthe specified range. In one embodiment, the one or more sweetenerscomprises about 0.1% to about 15%, about 0.1% to about 10%, or about0.1% to about 5% by weight of the matrix fill. In one aspect, the one ormore sweeteners comprises about 0.1%, about 0.15%, about 0.2%, about0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%,about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about0.8%, about 0.85%, about 0.9%, about 0.95%, or about 1% by weight of thematrix fill. In one aspect, the one or more sweeteners comprises about1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about8%, about 9%, about 10%, about 12%, or about 15% by weight of the matrixfill. In one aspect, the one or more sweeteners comprise about 0.5% byweight of the matrix fill. In another aspect, the one or more sweetenerscomprise about 0.2%, about 0.3%, about 0.4%, or about 0.7% by weight ofthe fill.

In another embodiment, the one or more sweeteners comprise sucralosehaving a weight percentage of about 0% to about 2% by weight of thematrix fill, including each integer within the specified range. Inanother embodiment, sucralose comprises about 0.1% to about 1.74%, about0.2% to about 1.5%, about 0.3% to about 1.5%, or about 0.4% to about 1%by weight of the matrix fill. In one aspect, sucralose comprises about0%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about1.5%; about 1.75%, or about 2% by weight of the matrix fill. In anotheraspect, sucralose comprises about 0.6% by weight of the fill. In anotheraspect, sucralose comprises about 0.5%, about 0.55%, or about 0.65% byweight of the fill.

In one embodiment, the sweeteners comprise mannitol having a weightpercentage of about 0% to about 5% by weight of the matrix fill,including each integer within the specified range. In one embodiment,mannitol comprises about 0.1% to about 4%, about 0.2% to about 3%, orabout 0.3% to about 2% by weight of the matrix fill. In one aspect,mannitol comprises about 0%, about 1%, about 2%, about 3%, about 4%, orabout 5% by weight of the matrix fill. In another aspect, mannitolcomprises about 0.5% by weight of the fill. In another aspect, mannitolcomprises about 0.3%, about 0.6%, or about 0.9% by weight of the fill.

In another embodiment, the sweeteners comprise thaumatin at a weightpercentage of about 0% to about 5% by weight of the matrix fill,including each integer within the specified range. In one embodiment,thaumatin comprises about 0.1% to about 4%, about 0.2% to about 3%, orabout 0.3% to about 2% by weight of the matrix fill. In one aspect,thaumatin comprises about 0%, about 1%, about 2%, about 3%, about 4%, orabout 5% by weight of the matrix fill. In another aspect, thaumatincomprises about 0.5% by weight of the fill. In another aspect, thaumatincomprises about 0.3%, about 0.6%, or about 0.9% by weight of the fill.

In another embodiment, the sweeteners comprise acesulfame potassium at aweight percentage of about 0% to about 5% by weight of the matrix fill,including each integer within the specified range. In one embodiment,acesulfame potassium comprises about 0.1% to about 4%, about 0.2% toabout 3%, or about 0.3% to about 2% by weight of the matrix fill. In oneaspect, acesulfame potassium comprises about 0%, about 1%, about 2%,about 3%, about 4%, or about 5% by weight of the matrix fill. In anotheraspect, acesulfame potassium comprises about 0.6% by weight of the fill.In another aspect, acesulfame potassium comprises about 0.3%, about0.5%, or about 0.9% by weight of the fill.

In another embodiment, the sweeteners comprise a glycyrrhizic acid salthaving a weight percentage of about 0% to about 5% by weight of thematrix fill, including each integer within the specified range. In oneembodiment, the glycyrrhizic acid salt comprises about 0.1% to about 4%,about 0.2% to about 3%, or about 0.3% to about 2% by weight of thematrix fill. In one aspect, the glycyrrhizic acid salt comprises about0%, about 1%, about 2%, about 3%, about 4%, or about 5% by weight of thematrix fill. In another aspect, the glycyrrhizic acid salt comprisesabout 0.5% by weight of the fill. In another aspect, the glycyrrhizicacid salt comprises about 0.3%, about 0.6%, or about 0.9% by weight ofthe fill.

In one embodiment, one or more flavorings comprise about 0.1% to about5% by weight of the matrix fill, including each integer within thespecified range. In another embodiment, the one or more flavoringscomprise about 0.1% to about 4.5%, about 0.1% to about 3.5%, or about0.1% to about 3% by weight of the matrix fill. In one aspect, theflavorings comprise about 0.01, about 1%, about 1.5%, about 1.6%, about2.0%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%,about 5.5%, or about 6% by weight of the matrix fill. In another aspect,the flavorings comprise about 4% by weight of the fill. In anotheraspect, the flavorings comprise about 0.01%, about 0.09%, about 1%,about %, or about 5% by weight of the fill.

In another embodiment, the flavorings comprise citric acid having aweight percentage of about 0.01% to about 3% by weight of the matrixfill, including each integer within the specified range. In oneembodiment, citric acid comprises about 0.25% to about 2.75%, about 0.5%to about 2.5%, or about 0.75% to about 2.25% by weight of the matrixfill. In one aspect, citric acid comprises about 0%, about 0.5%, about1%, about 1.5%, about 2%, about 2.5%, or about 3% by weight of thematrix fill. In another aspect, citric acid comprises about 1% by weightof the fill. In another aspect, citric acid comprises about 0.5%, about0.75%, about 1.25%, or about 1.5% by weight of the fill.

In another embodiment, the flavorings comprise lactic acid having aweight percentage of about 0% to about 3% by weight of the matrix fill,including each integer within the specified range. In one embodiment,lactic acid comprises about 0.25% to about 2.75%, about 0.5% to about2.5%, or about 0.75% to about 2.25% by weight of the matrix fill. In oneaspect, lactic acid comprises about 0%, about 0.5%, about 1%, about1.5%, about 2%, about 2.5%, or about 3% by weight of the matrix fill. Inanother aspect, lactic acid comprises about 1% by weight of the fill. Inanother aspect, lactic acid comprises about 0.5%, about 0.75%, about1.25%, or about 1.5% by weight of the fill.

In one embodiment, the flavorings comprise sodium citrate having aweight percentage of about 0% to about 3% by weight of the matrix fill,including each integer within the specified range. In anotherembodiment, sodium citrate comprises about 0.25% to about 2.75%, about0.5% to about 2.5%, or about 0.75% to about 2.25% by weight of thematrix fill. In one aspect, sodium citrate comprises about 0%, about0.5%, about 1%, about 1.5%, about 2%, about 2.5%, or about 3% by weightof the matrix fill. In another aspect, sodium citrate comprises about 1%by weight of the fill. In another aspect, sodium citrate comprises about0.5%; about 0.75%, about 1.25%, or about 1.5% by weight of the fill.

In another embodiment, a solvent comprises about 0% to about 15% byweight of the matrix fill, including each integer within the specifiedrange. In another embodiment, the solvent comprises about 0.5% to about13%, about 1% to about 11%, about 1.5% to about 9%, or about 2% to about6% by weight of the matrix fill. In another aspect, the solventcomprises about 0%, about 5%, about 10%, or about 15% by weight of thematrix fill. In another aspect, the solvent comprises about 5.5% byweight of the matrix fill. In another aspect, the solvent comprisesabout 4.5%, about 5%, about 6%, or about 6.5% by weight of the matrixfill.

In another embodiment, the solvent comprises water at a weightpercentage of about 0% to about 15% by weight of the matrix fill,including each integer within the specified range. In one embodiment,water comprises about 0.5% to about 13%, about 1% to about 11%, about1.5% to about 9%, or about 2% to about 6% by weight of the matrix fill.In another aspect, water comprises about 0%, about 5%, about 10%, orabout 15% by weight of the matrix fill. In another aspect, watercomprises 5.5% by weight of the matrix fill. In another aspect, watercomprises about 4.5%, about 5%, about 6%, or about 6.5% by weight of thematrix fill.

In another embodiment, the shell comprises one or more colorings.Typical food colorings such as FD&C food dyes or D&C dyes can be used inany combinations to create the desired color. Dyes can be used in weightpercentages from 0.0001% to 0.5%, including all integers and fractionswithin the specified ranges.

In one embodiment described herein, the compositions described hereincomprise one or more active pharmaceutical ingredients. In oneembodiment, one active pharmaceutical ingredient is the only activeingredient in the pharmaceutical composition. In another embodiment, oneor more active pharmaceutical ingredients or drugs are included in thepharmaceutical composition. In another embodiment, the activepharmaceutical ingredient can be an active pharmaceutical ingredient, aderivative thereof, or combinations thereof.

In one embodiment, the compositions described herein comprise one ormore active pharmaceutical ingredients useful for treating, retardingthe progression of, delaying the onset of, prophylaxis of, ameliorationof, or reducing the symptoms of pain, inflammation, fever, or symptomsstemming from cough or cold. In one embodiment described herein, theactive pharmaceutical ingredient comprises one or more of astemizole,azelastine, azatadine, brompheniramine, carbinoxamine, cetirizine,chlorpheniramine, clemastine, cyproheptadine, desloratadine,dexbrompheniramine, dexchlorpheniramine, diphenhydramine, fexofenadine,hydroxyzine, levocetirizine, loratadine, phenindamine, pheniramine,phenyltoloxamine, promethazine, pyrilamine, terfenadine, tripelennamine,triprolidine, acetyl dihydrocodeine, benproperine, benzonatate,benzylmorphine, bibenzonium bromide, butamirate, butorphanol,carbetapentane, chlophedianol, clobutinol, clofedanol, cloperastine,codeine, dextromethorphan, diacetylmorphine, dibunate, dihydrocodeine,dimemorfan, dimethoxanate, diphenhydramine, dropropizine, droxypropine,ethylmorphine, fedrilate, glaucine, hydrocodone, hydromorphone,isoaminile, laudanum, levodropropizine, levomethadone, levopropoxyphene,meprotixol, methadone, morclofone, nepinalone, nicocodine, nicodicodine,normethadone, noscapine, oxeladin, oxolamine, pentoxyverine, pholcodine,pipazetate, piperidione, prenoxdiazine, tipepidine, zipeprol,acetylcysteine, althea root, ambroxol, antimony pentasulfide,bromhexine, carbocisteine, cineole, combinations, combinations,creosote, dembrexine hydrochloride, domiodol, dornase alfa, eprazinone,erdosteine, guaiacolsulfonate, guaifenesin, hederae helicis folium,ipecacuanha, letosteine, levo verbenone, mannitol, mesna, neltenexine,potassium iodide, senega, sobrerol, stepronin, tiopronin, tyloxapol, orcombinations thereof. In one aspect, the active pharmaceuticalingredient comprises one or more of dextromethorphan hydrobromide,menthol, or combinations thereof.

In one embodiment described herein, the active pharmaceutical ingredientis an anti-allergy agent. Exemplary anti-allergy agents includepseudoephedrine, cetirizine, loratadine, fexofenadine, diphenhydramine,levocetirizine, desloratadine, or combinations thereof.

In one embodiment described herein, the active pharmaceutical ingredientis an oral rinsing agent. Exemplary oral rinsing agents include phenol,ethanol, thymol, eucalyptol, ethanol, methyl salicylate, chlorhexidinegluconate, cetylpyridinium chloride, hexetidine, triclosan, hydrogenperoxide, domiphen bromide, or combinations thereof. In one embodimentdescribed herein, the active pharmaceutical ingredient comprises an oralrinsing agent comprising one or more of ethanol (about 20% to about 30%)menthol (0.042%), thymol (0.064%), methyl salicylate (0.06%), andeucalyptol (0.092%).

In one embodiment described herein, the active pharmaceutical ingredientis an antidiarrheal or antacid comprising bismuth subsalicylate,loperamide hydrochloride, aluminum hydroxide, magnesium hydroxide,simethicone, aluminum carbonate, calcium carbonate, sodium bicarbonate,magnesium aluminum silicate, hydrotalcite, magaldrate, cimetidine,famotidine, nizatidine, ranitidine, lansoprazole, omeprazole,esomeprazole, rabeprazole, pantoprazole, dexlansoprazole, orcombinations thereof. In one embodiment described herein, the activepharmaceutical ingredient comprises one or more of bismuth subsalicylate(˜17.6 mg), benzoic acid, D&C Red No. 22, D&C Red No. 28, flavoring,magnesium aluminum silicate, methylcellulose, sodium saccharin,salicylic acid, sodium salicylate, sorbic acid, and water.

In another embodiment, the active pharmaceutical ingredient is anirritable bowel syndrome therapeutic. Exemplary non-limiting activepharmaceutical ingredients useful for the treatment of irritable bowelsyndrome comprise antidiarrheals such as atropine, diphenoxylate(Lomotil®), dicyclomine (Bentyl®), loperamide (Imodium®), rifaximin(Xifaxan®), alosetron (Lotronex®); bile acid binding agents such ascholestyramine (Prevailite®); constipation therapeutics such aslinaclotide (Linzess®) or lubiprostone (Amitiza) or combinationsthereof.

In one embodiment described herein, the active pharmaceutical ingredientis a constipation therapeutic such as linaclotide (Linzess®) orlubiprostone (Amitiza®), methylcellulose, polycarbophil, psyllium,mineral oil, glycerol, docusate sodium, sodium bicarbonate, sodiumphosphate, magnesium citrate, magnesium oxide, magnesium sulfate,bisacodyl, sennosides, senna, castor oil or combinations thereof.

In another embodiment described herein, the active pharmaceuticalingredient comprises one or more corticosteroids for treatinginflammatory diseases and conditions and inflammation of thegastrointestinal tract, including but not limited to esophagealinflammation. In one embodiment described herein, the activepharmaceutical ingredient comprises one or more corticosteroidsincluding but not limited to alclometasone, amcinonide, beclometasone,betamethasone, budesonide, ciclesonide, clobetasol, clobetasone,clocortolone, cloprednol, cortivazol, deflazacort, deoxycorticosterone,desonide desoximetasone, dexamethasone, diflorasone, diflucortolone,difluprednate, fluclorolone, fludrocortisone, fludroxycortide,flumetasone, flunisolide, fluocinolone acetonide, fluocinonide,fluocortin, fluocortolone, fluorometholone, fluperolone, fluticasone,fluticasone propionate, fluprednidene, formocortal, halcinonide,halometasone, hydrocortisone aceponate, hydrocortisone buteprate,hydrocortisone butyrate, loteprednol, medrysone, meprednisone,methylprednisolone, methylprednisolone aceponate, mometasone furoate,paramethasone, prednicarbate, prednisone, prednisolone, prednylidene,rimexolone, tixocortol, triamcinolone, ulobetasol, combinations thereof,or pharmaceutically acceptable salts, or esters thereof.

In another embodiment described herein, the active pharmaceuticalingredient comprises one or more of 5-fluorouracil,5-fluorodeoxyuridine, capecitabine, derivatives thereof, or combinationsthereof for treating neoplasia, including but not limited to head andneck neoplasia.

In another embodiment described herein, the active pharmaceuticalingredient comprises one or more of calcium supplements or calcimimeticsincluding but not limited to cinacalcet, derivatives thereof, orcombinations thereof for treating hyperthyroidism, hypercalcemia,hyperparathyroidism, parathyroid carcinoma, or a combination thereof.

In some embodiments, the active pharmaceutical ingredient is a sleepaid. Examples of sleep aids include, but are not limited to doxylamine,diphenhydramine hydrochloride, melatonin, l-theanine, or combinationsthereof.

In some embodiments, the active pharmaceutical ingredient is an oralsaliva substitute, such as, for example: monofluorophosphate,lactoferrin, lysozyme, lactoperoxidase, glucose oxidase, mutanase,dextranase, glycerol, or combinations thereof.

In some embodiments, the active pharmaceutical ingredient is ateeth-bleaching or teeth-whitening agent, including but not limited tocarbamide peroxide, sodium bicarbonate, hydrated silica, silicondioxide, polyvinylpyrrolidone, potassium nitrate, sodiummonofluorophosphate, sodium tripolyphosphate, strontium chloride, orcombinations thereof.

In another embodiment, the active pharmaceutical ingredient is a toothenamel-enhancing agent. Exemplary tooth enamel enhancing agents includepotassium nitrate, strontium acetate, strontium chloride, calcium sodiumphosphosilicate, or combinations thereof.

In another embodiment, the active pharmaceutical ingredient is an oralanesthetic, including but not limited to benzocaine, lidocaine, cloveoil, or combinations thereof.

In one embodiment, the active pharmaceutical ingredient is aneffervescent including but not limited to sodium bicarbonate, citricacid, tartaric acid, or combinations thereof. Effervescent may becombined with one or more cold, cough, allergy, nasal decongestant,antitussive, expectorant, antihistamine, stimulant, sedative,anti-inflammatory, antibiotic, anti-viral, anti-asthmatic,anti-migraine, hypnotic, narcotic analgesic, or narcotic antagonistactive pharmaceutical ingredients, or further combinations thereof.

In one embodiment described herein, the active pharmaceutical ingredientis one or more non-steroidal anti-inflammatory drugs (NSAID).Non-limiting examples of NSAID active pharmaceutical ingredientscomprise aspirin, ibuprofen, aceclofenac, acemetacin, aloxiprin,azapropazone, benorilate, bromfenac, carprofen, celecoxib, cholinemagnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib,fisalamine, fenbufen, fenoprofen, flurbiprofen, indometacin, ketoprofen,ketorolac, lornoxicam, loxoprofen, meloxicam, meclofenamic acid,mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesiumsalicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone,paracetamol, parecoxib, phenylbutazone, piroxicam, salicyl salicylate,sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid,tolmetin, valdecoxib, or combinations thereof.

In another embodiment, suitable active pharmaceutical ingredients cancomprise analgesics, such as, for example: acetylsalicylic acid,aloxiprin, aminophenazone, anilides, benorilate, benzomorphanderivatives, bezitramide, bucetin, buprenorphine, butorphanol,carbasalate calcium, choline salicylate, codeine, dextromoramide,dextropropoxyphene, dezocine, diamorphine, diflunisal, dihydrocodeine,dihydrocodone, dihydromorphine, diphenylpropylamine derivatives,dipyrocetyl, ethenzamide, fentanyl, floctafenine, flupirtine, glafenine,guacetisal, hydrocodone, hydrocodone bitartrate, hydromorphone,hydromorphone hydrochloride, imidazole salicylate, ketobemidone,metamizole sodium, methadone, morphinan derivatives, morphine, morphinesulphate pentahydrate, morphine-6-glucuronode, morpholine salicylate,nalbuphine, natural opium alkaloids, nefopam, nicomorphine, nifenazone,norhydrocodone, noroxycodone, opioids, opium, oripavine derivatives,oxycodeine, oxycodone, oxycodone hydrochloride, oxymorphone,papaveretum, pentazocine, pethidine, phenacetin, phenazocine, phenazone,phenylpiperidine derivatives, piritramide, potassium salicylate,propacetamol, propyphenazone, pyrazolones, rimazolium, salicylamide,salicylic acid derivatives, salsalate, sodium salicylate, tapentadol,tilidine, tramadol, viminol, ziconotide, or combinations thereof.

In another embodiment, the active pharmaceutical ingredient disclosedherein includes an opioid, the opioid is selected from buprenorphine,codeine, dextromoramide, dihydrocodeine, fentanyl, hydrocodone,hydromorphone, morphine, pentazocine, oxycodeine, oxycodone,oxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronode,tramadol, tapentadol, dihydromorphine, or combinations thereof.

In one embodiment described herein, the active pharmaceutical ingredientis a probiotic. Exemplary probiotics include Bifidobacterium infantis35624, Bifidobacterium lactis HN019, Lactobacillus reuteri ATCC55730,Lactobacillus rhamnosus, Lactobacillus casei DN-114 001, Bifidobacteriumlactis Bb-12, or combinations thereof.

In another embodiment, the active pharmaceutical ingredient comprisesactive drug substances used in the treatment of addictive disorders,such as, for example: nicotine, nicotine polacrilex, bupropion,varenicline, disulfiram, calcium carbimide, acamprosate, naltrexone,buprenorphine, methadone, levacetylmethadol, lofexidine, betahistine,cinnarizine, flunarizine, acetylleucine, gangliosides, gangliosidederivatives, tirilazad, riluzole, xaliproden, hydroxybutyric acid,amifampridine, or combinations thereof. In one embodiment describedherein, the active pharmaceutical ingredient comprises one or more ofnicotine (˜2 mg), acesulfame potassium, magnesium oxide, menthol,peppermint oil, xylitol, sodium bicarbonate, sodium carbonate, orcombinations thereof.

In another embodiment, the active pharmaceutical ingredient can comprisethose found in energy drinks, including caffeine, taurine, Ginko biloba,glucuronolactone, inositol, niacin, niacinamide, D-pantothenol, Panaxginseng root extract, pyridoxine HCl, vitamin B12, cyanocobalamin,riboflavin, guarana, L-carnitine, or combinations thereof.

In another embodiment, the pharmaceutical composition can comprisevitamins or minerals. “Vitamins” as used herein refers to nutraceuticalsor pharmaceutical ingredients comprising organic substances that aretypically considered essential for the normal growth and activity of asubject (e.g., a human or non-human animal patient to whom thecomposition is to be administered). Non-limiting examples of vitaminsinclude, but are not limited to vitamin A (retinol), B1 (thiamine), B2(riboflavin), B complex, B6 (pyridoxine), B12 (cobalamin), C (ascorbicacid), D (cholecalciferol), E (tocopherol), F (linoleic acid), G, H(biotin), and K, and choline, folic acid, inositol, niacin, pantothenicacid, para-aminobenzoic acid or combinations thereof.

In some embodiments, the active pharmaceutical ingredient is apharmaceutical a nutraceutical. Examples of nutraceuticals include, butare not limited to, amino acids, terpenoids (e.g., carotenoid terpenoidsand non-carotenoid terpenoids), herbal supplements, homeopathicsupplements, glandular supplements, polyphenolics, flavonoidpolyphenolics, phenolic acids, curcumin, resveratrol, lignans,glucosinolates, isothiocyanates, indoles, thiosulfinates, phytosterols,anthraquinones, capsaicin, piperine, chlorophyll, betaine, oxalic acid,acetyl-L-carnitine, allantoin, androstenediol, androstendione, betaine(trimethylglycine), caffeine, calcium pyruvate (pyruvic acid),carnitine, carnosine, carotene, carotenoid, choline, chlorogenic acid,cholic acid, chondroitin sulfate, chondroitin sulfate, cholestan,chrysin, coenzyme Q10, conjugated linoleic acid, corosolic acid,creatine, dehydroepiandrosterone, dichlorophen, diindolymethane,dimethylglycine, dimercapto succinic acid, ebselen, ellagic acid,enzymes, fisetin, formononetin, glucaric acid (glucarate), glucosamine(HCl or sulfate), glucosamine (N-acetyl), glutathione, hesperidine,hydroxy-3-methylbutyric acid, 5-hydroxytryptophan, indole-3-carbinol,inositol, isothiocyanates, linolenic acid-gamma, lipoic acid (alpha),melatonin, methylsulfonylmethane, minerals, naringin, pancreatin,para-aminobenzoic acid, paraben (methyl or propyl), phenolics,phosphatidylcholine, phosphatidylserine, phospholipids, phytosterols,progesterone, pregnenolone, omega-3 fatty acids, quercetin, resveratrol,D-ribose, rutin, S-adenosylmethionine, salicylic acid, sulforaphane,tartaric acid, taxifolin, tetrahydropalmatine, theophyline, theobromine,tigogenin, troxerutin, tryptophan, tocotrienol (alpha, beta, and gamma),zeaxanthin, Gingko biloba, ginger, cat's claw, hypericum, Aloe vera,evening primrose, garlic, ginseng, capsicum, dong quai, ginseng,feverfew, fenugreek, echinacea, green tea, marshmallow, saw palmetto,tea tree oil, fish oil, psyllium, kava-kava, licorice root, Mahoniaaquifolium, hawthorne, tumeric, witch hazel, yohimbe, aleurain,mistletoe, bilberry, bee pollen, peppermint oil, beta-carotene,genistein, lutein, lycopene, polyphenols, and the like. Further examplesof suitable nutraceuticals include those listed in Handbook ofNutraceuticals and Functional Foods, Robert E. C. Wildman, Ed., CRCPress (2001), which is incorporated by reference herein for theteachings related to nutraceuticals.

In another embodiment, the active pharmaceutical ingredients describedherein may comprise pharmaceutically acceptable salts of any of theabove mentioned active drug substances. The term “pharmaceuticallyacceptable salts” of an active pharmaceutical ingredient includes alkalimetal salts such as, for example, sodium or potassium salts, alkalineearth metal salts such as, for example, calcium and magnesium salts, andsalts with organic or inorganic acid such as, for example, hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,citric acid, formic acid, maleic acid, succinic acid, tartaric acid,methanesulphonic acid, toluenesulphonic acid etc. In another embodiment,the active pharmaceutical ingredient may also be in the form ofpharmaceutically acceptable salts, uncharged or charged molecules,molecular complexes, solvates, or anhydrates thereof, and, if relevant,single isomers, enantiomers, racemic mixtures, or mixtures thereof.

In another embodiment, the active pharmaceutical ingredient may be inany of its crystalline, polymorphous, semi-crystalline, amorphous orpolyamorphous forms or mixtures thereof.

In another embodiment, an active pharmaceutical ingredient comprisesabout 0% to about 6% by weight of the matrix fill, including eachinteger within the specified range. In another embodiment, the activepharmaceutical ingredient comprises about 0.25% to about 5%, about 0.5%to about 4%, about 0.75% to about 3%, or about 1% to about 2% by weightof the matrix fill. In one aspect, the active pharmaceutical ingredientcomprises about 0%, about 1%, about 2%, about 3%, about 4%, about 5%, orabout 6% by weight of the matrix fill. In one aspect, the activepharmaceutical ingredient comprises about 1.6% by weight of the fill. Inone aspect, the active pharmaceutical ingredient comprises about 1%,about 1.5%, about 2%, or about 2.5% by weight of the fill.

In another embodiment, the active pharmaceutical ingredient comprisesdextromethorphan hydrobromide having a weight percentage of about 0% toabout 5% by weight of the matrix fill, including each integer within thespecified range. In one aspect, dextromethorphan hydrobromide comprisesabout 0.25% to about 5%, about 0.5% to about 4%, about 0.75% to about3%, or about 0.75% to about 2% by weight of the matrix fill. In anotheraspect, dextromethorphan hydrobromide comprises about 0%, about 1%,about 2%, about 3%, about 4%, or about 5% by weight of the matrix fill.In one aspect, dextromethorphan hydrobromide comprises about 1% byweight of the fill. In one aspect, dextromethorphan hydrobromidecomprises about 0.50%, about 0.74%, or about 1.25% by weight of thematrix fill.

In another embodiment, the active pharmaceutical ingredient comprisesmenthol at a weight percentage of about 0% to about 2% by weight of thematrix fill, including each integer within the specified range. In oneaspect, menthol comprises about 0.1% to about 1.75%, about 0.2% to about1.5%, about 0.3% to about 1.25%, or about 0.4% to about 1% by weight ofthe matrix fill. In another aspect, menthol comprises about 0%, about0.25%, about 0.5%, about 0.75%, about 1.25%, about 1.5%; about 1.75%; orabout 2% by weight of the matrix fill. In one aspect, menthol comprisesabout 0.5% by weight of the fill. In one aspect, menthol comprises about0.40%, about 0.45%, about 0.55% or about 0.6% by weight of the fill.

In another embodiment, the ratio of the active pharmaceutical ingredientto the remaining fill components in the matrix fill comprises about 1:10to about 1:100, including each ratio within the specified range. In oneembodiment, the ratio of active pharmaceutical ingredient to theremaining fill components in the fill is about 1:20 to about 1:80, about1:30 to about 1:70, or about 1:40 to about 1:70. In one aspect, theratio of active pharmaceutical ingredient to the remaining fillcomponents in the matrix fill is about 1:10, about 1:20, about 1:30,about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90,or about 1:100. In another aspect, the ratio of active pharmaceuticalingredient to the remaining fill components in the fill is about 1:63.In another aspect, the ratio of active pharmaceutical ingredient to theremaining fill components in the matrix fill is about 1:60, about 1:62,about 1:64, or about 1:65.

In another embodiment, the ratio of the active pharmaceutical ingredientto the total hydrophilic vehicle in the matrix fill comprises about 1:10to about 1:50, including each ratio within the specified range. In oneembodiment, the ratio of active pharmaceutical ingredient to the totalhydrophilic vehicle in the matrix fill comprises about 1:15 to about1:45, or about 1:20 to about 1:40. In one aspect, the ratio of activepharmaceutical ingredient to the total hydrophilic vehicle is about1:10, about 1:20, about 1:30, about 1:40, or about 1:50. In anotheraspect, the ratio of active pharmaceutical ingredient to the totalhydrophilic vehicle in the matrix fill is about 1:24. In another aspect,the ratio of active pharmaceutical ingredient to the total hydrophilicvehicle in the matrix fill is about 1:20, about 1:21, about 1:22, about1:23, about 1:25, or about 1:26.

In another embodiment, the ratio of the active pharmaceutical ingredientto the propylene glycol in the matrix fill comprises about 1:1 to about1:10, including each ratio within the specified range. In oneembodiment, the ratio active pharmaceutical ingredient to propyleneglycol in the fill is about 1:1 to about 1:9, about 1:2 to about 1:8,about 1:4 to about 1:7, or about 1:5 to about 1:6. In one aspect, theratio of active pharmaceutical ingredient to propylene glycol in thematrix fill is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, orabout 1:6. In another aspect, the ratio of active pharmaceuticalingredient to propylene glycol in the fill is about 1:5. In anotheraspect, the ratio of active pharmaceutical ingredient to propyleneglycol in the matrix is about 1:2, about 1:3, about 1:4, or about 1:6.

In another embodiment described herein, the total mass of the matrixfill of the pharmaceutical composition described herein that comprisesan active pharmaceutical ingredient described herein is from about 400mg to about 1600 mg, including all integers within the specified range.In one aspect, the total mass of the matrix fill mass is about 400 mg.In another aspect, the total mass of the matrix fill mass is about 500mg. In one aspect, the total mass of the matrix fill mass is about 600mg. In another aspect, the total mass of the matrix fill mass is about700 mg. In another aspect, the total mass of the matrix fill mass isabout 800 mg. In another aspect, the total mass of the matrix fill massis about 900 mg. In another aspect, the total mass of the matrix fillmass is about 1000 mg. In another aspect, the total mass of the matrixfill mass is about 1100 mg. In another aspect, the total mass of thematrix fill mass is about 1200 mg. In another aspect, the total mass ofthe matrix fill mass is about 1300 mg. In another aspect, the total massof the matrix fill mass is about 1400 mg. In another aspect, the totalmass of the matrix fill mass is about 1500 mg. In another aspect, thetotal mass of the matrix fill mass is about 1600 mg.

TABLE 3 Exemplary Liquisoft Composition Weight Percentage ComponentExemplary Component (%) Capsule Shell Formulation Polymers Gelatin, 150Bloom 19.3 Gelatin, 100 Blom 8.3 Hydrolyzed Collagen 4.9 PlasticizersMaltitol 16.8 Glycerol 24 Xylitol 2.6 Sweetener(s) Sucralose 0.2 PolymerCitric Acid 0.5 Modifiers Coloring FD&C Food colorings 0.1 Solvent Water23 TOTAL 100% Matrix Fill Formulation Hydrophilic Propylene Glycol 8.0Vehicles Polyethylene Glycol 400 19.5 Polyvinylpyrrolidone K30 1.2Flavorings Citric Acid 1.0 Lactic Acid 1.0 Sodium Citrate — OrangeFlavor PB72 1.6 Sweeteners Mannitol — Acesulfame potassium 0.6Glycyrrhizic acid salts — (MagnaSweet ®) Maltitol 55.1 Sucralose 0.6Excipients e.g., γ-cyclodextrin 2.2 Solvent Water 7.5 ActiveDextromethorphan 1.6 Pharmaceutical Hydrobromide Ingredients Menthol 0.1(API) TOTAL 100%

One embodiment described herein is an oral pharmaceutical compositionsuitable for chewing, sucking, or buccal dissolution comprising thecomposition in Table 3.

In one embodiment, the pharmaceutical composition described herein,comprises an active pharmaceutical ingredient of about 0.5 mg to about5000 mg, including each integer within the specified range.

In one embodiment, the pharmaceutical composition described herein,comprises an active pharmaceutical ingredient of about 0.5 mg, about0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg,about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg,about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg,about 9.75 mg, or about 10 mg, or even greater.

In another embodiment described herein, the pharmaceutical compositiondescribed herein, comprises an active pharmaceutical ingredient of about10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg,about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about970 mg, about 980 mg, about 990 mg, or about 1000 mg, or even greater.

In another embodiment described herein, the pharmaceutical compositiondescribed herein, comprises an active pharmaceutical ingredient of about1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg,about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg,about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg,about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850mg, about 2900 mg, about 2950 mg, about 3000 mg, about 3050 mg, about3100 mg, about 3150 mg, about 3200 mg, about 3250 mg, about 3300 mg,about 3350 mg, about 3400 mg, about 3450 mg, about 3500 mg, about 3550mg, about 3600 mg, about 3650 mg, about 3700 mg, about 3750 mg, about3800 mg, about 3850 mg, about 3900 mg, about 3950 mg, about 4000 mg,about 4050 mg, about 4100 mg, about 4150 mg, about 4200 mg, about 4250mg, about 4300 mg, about 4350 mg, about 4400 mg, about 4450 mg, about4500 mg, about 4550 mg, about 4600 mg, about 4650 mg, about 4700 mg,about 4750 mg, about 4800 mg, about 4850 mg, about 4900 mg, about 4950mg, or about 5000 mg, or even greater.

In another embodiment described herein, the dosage form can beadministered, for example, 1×, 2×, 3×, 4×, 5×, 6×, 7×, or 8×, per day.One or more dosage form can be administered, for example, for 1, 2, 3,4, 5, 6, 7 days, or even longer. One or more dosage forms can beadministered, for example, for 1, 2, 3, 4 weeks, or even longer. One ormore dosage forms can be administered, for example, for 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12 months, or even longer. One or more dosage formscan be administered until the patient, subject, mammal, mammal in needthereof, human, or human in need thereof, does not require treatment,prophylaxis, or amelioration of any disease or condition such as, forexample, pain. In some aspects, the dosage form may be co-administeredwith other pharmaceutical compositions until the patient, subject,mammal, mammal in need thereof, human, or human in need thereof, doesnot require treatment, prophylaxis, or amelioration of any disease orcondition including but not limited to pain or illness.

In one embodiment described herein, the active pharmaceutical ingredientcomprises dextromethorphan hydrobromide having a dose of about 5 mg toabout 200 mg, including all integers within the specified range. In oneaspect, the dose of dextromethorphan hydrobromide is about 5 mg. In oneaspect, the dose of dextromethorphan hydrobromide is about 10 mg. Inanother aspect, the dose of dextromethorphan hydrobromide is about 15mg. In another aspect, the dose of dextromethorphan hydrobromide isabout 20 mg. In another aspect, the dose of dextromethorphanhydrobromide is about 25 mg, about 30 mg, about 35 mg, about 40 mg,about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg,about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg,about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg,about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, orabout 200 mg.

In one embodiment described herein, the active pharmaceutical ingredientcomprises dextromethorphan hydrobromide and menthol, wherein the dose ofdextromethorphan hydrobromide is as described of, and the dose ofmenthol is about 1 mg to about 10 mg, including all integers within thespecified range. In one aspect, the dose of menthol is about 0.09 mg. Inone aspect, the dose of menthol is about 1 mg. In another aspect, thedose of menthol is about 2 mg. In another aspect, the dose of menthol isabout 3 mg. In another aspect, the dose of menthol is about 3 mg. Inanother aspect, the dose of menthol is about 4 mg. In another aspect,the dose of menthol is about 5 mg. In another aspect, the dose ofmenthol is about 5 mg. In another aspect, the dose of menthol is about 6mg. In another aspect, the dose of menthol is about 7 mg. In anotheraspect, the dose of menthol is about 8 mg. In another aspect, the doseof menthol is about 9 mg. In another aspect, the dose of menthol isabout 10 mg.

In one embodiment, the total dosage of dextromethorphan hydrobromide andmenthol administered in a 24-hour period is about 20 mg to about 200 mg.In one aspect, the total dosage of dextromethorphan hydrobromide andmenthol administered in a 24-hour period is about 30 mg, about 40 mg,about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about185 mg, about 190 mg, about 195 mg, or about 200 mg.

In one embodiment, the total dosage of dextromethorphan hydrobromide andmenthol administered in a 24-hour period is about 20 mg to about 160 mgper 24-hour period including all iterations of integers within thespecified range. In another embodiment, the total dosage ofdextromethorphan hydrobromide and menthol administered in a 24-hourperiod is about 20 mg to about 40 mg per 24-hour period including alliterations of integers within the specified range. In anotherembodiment, the total dosage of dextromethorphan hydrobromide andmenthol administered in a 24-hour period is about 30 mg to about 50 mgper 24-hour period including all iterations of integers within thespecified range. In another embodiment, the total dosage ofdextromethorphan hydrobromide and menthol administered in a 24-hourperiod is about 40 mg to about 60 mg per 24-hour period including alliterations of integers within the specified range. In anotherembodiment, the total dosage of dextromethorphan hydrobromide andmenthol administered in a 24-hour period is about 50 mg to about 80 mgper 24-hour period including all iterations of integers within thespecified range. In another embodiment, the total dosage ofdextromethorphan hydrobromide and menthol administered in a 24-hourperiod is about 60 mg to about 90 mg per 24-hour period including alliterations of integers within the specified range. In anotherembodiment, the total dosage of dextromethorphan hydrobromide andmenthol administered in a 24-hour period is about 70 mg to about 100 mgper 24-hour period including all iterations of integers within thespecified range. In another embodiment, the total dosage ofdextromethorphan hydrobromide and menthol administered in a 24-hourperiod is about 80 mg to about 110 mg per 24-hour period including alliterations of integers within the specified range. In anotherembodiment, the total dosage of dextromethorphan hydrobromide andmenthol administered in a 24-hour period is about 90 mg to about 120 mgper 24-hour period including all iterations of integers within thespecified range. In another embodiment, the total dosage ofdextromethorphan hydrobromide and menthol administered in a 24-hourperiod is about 100 mg to about 130 mg per 24-hour period including alliterations of integers within the specified range. In anotherembodiment, the total dosage of dextromethorphan hydrobromide andmenthol administered in a 24-hour period is about 110 mg to about 140 mgper 24-hour period including all iterations of integers within thespecified range. In another embodiment, the total dosage ofdextromethorphan hydrobromide and menthol administered in a 24-hourperiod is about 120 mg to about 150 mg per 24-hour period including alliterations of integers within the specified range. In anotherembodiment, the total dosage of dextromethorphan hydrobromide andmenthol administered in a 24-hour period is about 130 mg to about 160 mgper 24-hour period including all iterations of integers within thespecified range.

In another embodiment, the total dosage of dextromethorphan hydrobromideand menthol administered in a 24-hour period is about 20 mg to about 160mg and is effective for the treatment of cough or illness isadministered in equal daily doses. In one aspect, 20 mg ofdextromethorphan hydrobromide and menthol is administered 2 times dailyfor a total of 40 mg to reach a desired therapeutic efficacy. In anotheraspect, 20 mg of dextromethorphan and menthol is administered 4 timesdaily for a total of 80 mg to reach a desired therapeutic efficacy. Inanother aspect, 20 mg of dextromethorphan and menthol is administered 6times daily for a total of 120 mg to reach a desired therapeuticefficacy. In another aspect, 20 mg of dextromethorphan and menthol isadministered 8 times daily for a total of 160 mg to reach a desiredtherapeutic efficacy.

In one embodiment, the dosage can contain an amount of dextromethorphanhydrobromide effective for treatment, amelioration, prophylaxis, orreducing the onset of or symptoms of mild, moderate, or severe cold andcough.

In another embodiment, the dosage can contain an amount ofdextromethorphan hydrobromide and an amount of one or more nasaldecongestants, antitussives, expectorants, or antihistamines, or amixture or combination thereof for the treatment, amelioration,prophylaxis, or reducing the onset of or symptoms of a cough or cold.

In one embodiment described herein, the active pharmaceutical ingredientcomprises thymol having a dose of about 0.0005 mg to about 0.002 mg,including all integers within the specified range. In one aspect, thedose of thymol is about 0.0005 mg. In one aspect, the dose of thymol isabout 0.00075 mg. In another aspect, the dose of thymol is about 0.001mg. In another aspect, the dose of thymol is about 0.0015 mg. In anotheraspect, the dose of thymol is about 0.002 mg. In another aspect, thedose of thymol is about 0.0005 mg, about 0.0006 mg, about 0.0007 mg,about 0.0008 mg, about 0.0009 mg, about 0.001 mg, or about 0.002 mg.

In one embodiment described herein, the active pharmaceutical ingredientcomprises thymol and menthol, wherein the dose of thymol is as describedof, and the dose of menthol is about 1 mg to about 10 mg, including allintegers within the specified range. In one aspect, the dose of mentholis about 0.09 mg. In one aspect, the dose of menthol is about 1 mg. Inanother aspect, the dose of menthol is about 2 mg. In another aspect,the dose of menthol is about 3 mg. In another aspect, the dose ofmenthol is about 3 mg. In another aspect, the dose of menthol is about 4mg. In another aspect, the dose of menthol is about 5 mg. In anotheraspect, the dose of menthol is about 5 mg. In another aspect, the doseof menthol is about 6 mg. In another aspect, the dose of menthol isabout 7 mg. In another aspect, the dose of menthol is about 8 mg. Inanother aspect, the dose of menthol is about 9 mg. In another aspect,the dose of menthol is about 10 mg.

In one embodiment, the dosage can contain an amount of thymol effectivefor treatment, amelioration, prophylaxis, or reducing the onset of orsymptoms of dry mouth, halitosis, stained teeth, oral pain, or loss ofenamel.

In another embodiment, the dosage can contain an amount of thymol and anamount of one or more chlorohexidine, ethanol or a mixture orcombination thereof for the treatment, amelioration, prophylaxis, orreducing the onset of or symptoms of dry mouth, halitosis, stainedteeth, oral pain, or loss of enamel.

In one embodiment described herein, the active pharmaceutical ingredientcomprises nicotine polacrilex having a dose of about 2 mg to about 80mg, including all integers within the specified range. In one aspect,the dose of nicotine polacrilex is about 10 mg to about 70 mg, about 20mg to about 60 mg, or about 30 mg to about 50 mg. In another aspect, thedose of nicotine polacrilex is about 2 mg, about 4 mg, about 6 mg, about8 mg, about 10 mg, about 20 mg, about 40 mg, about 60 mg, or about 80mg.

In one embodiment, the dosage can contain an amount of nicotinepolacrilex effective for treatment, amelioration, prophylaxis, orreducing the onset of or symptoms of urge to smoke.

In another embodiment, the dosage can contain an amount of nicotinepolacrilex and an amount of one or more bupropion, varenicline or amixture or combination thereof for the treatment, amelioration,prophylaxis, or reducing the onset of symptoms of urge to smoke.

In one embodiment described herein, the active pharmaceutical ingredientcomprises bismuth subsalicylate having a dose of about 44 mg to about4,192 mg, including all integers within the specified range. In oneaspect, the dose of bismuth subsalicylate is about 50 mg to about 4000mg, about 75 mg to about 3,500 mg, or about 100 mg to about 3,000 mg. Inanother aspect, the dose of bismuth subsalicylate is about 50 mg, about100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 1,500 mg,about 2,000 mg, about 2,500 mg, about 3,000 mg about 3,500 mg, or about4,000 mg.

In one embodiment, the dosage can contain an amount of bismuthsubsalicylate effective for treatment, amelioration, prophylaxis, orreducing the onset of inflammation of the gastrointestinal tract,neoplasia, hyperthyroidism, hypercalcemia, hyperparathyroidism,parathyroid carcinoma, indigestion, heartburn, irritable bowels,constipation, or diarrhea.

In another embodiment, the dosage can contain an amount of bismuthsubsalicylate and an amount of one or more of cimetidine, ranitidine,famotidine, ondansetron, omeprazole, lansoprazole, rabeprazole,esomeprazole, pantoprazole, calcium supplements, calcium hydroxide,aluminum hydroxide, magnesium hydroxide, or a mixture or combinationthereof for the treatment, amelioration, prophylaxis, or reducing theonset of inflammation of the gastrointestinal tract, neoplasia,hyperthyroidism, hypercalcemia, hyperparathyroidism, parathyroidcarcinoma, indigestion, heartburn, irritable bowels, constipation,diarrhea.

The concentration of the active pharmaceutical ingredient in thepharmaceutical composition depends on the specific active pharmaceuticalingredient, the disease to be treated, the condition of the patient, theage, and gender of the patient, etc. The active pharmaceuticalingredient may be a well-known active pharmaceutical ingredient and aperson having ordinary skill in the art will be able to find informationas to the dosage of each active drug substance and, accordingly, willknow how to determine the amount of each active drug substance in thepharmaceutical composition.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,reducing the symptoms of, or promoting health, including but not limitedto of one or more of pain, inflammation, cough, cold, fever, flu,inflammation of the gastrointestinal tract, neoplasia, hyperthyroidism,hypercalcemia, hyperparathyroidism, parathyroid carcinoma, indigestion,heartburn, irritable bowels, constipation, diarrhea, insomnia, drymouth, halitosis, stained teeth, oral pain, loss of enamel, urge tosmoke, fatigue, or malaise comprising administering to a subject in needthereof an oral pharmaceutical composition suitable for chewing,sucking, or buccal dissolution as described herein.

Another embodiment described herein is a composition for treating,retarding the progression of, prophylaxis of, delaying the onset of,ameliorating, reducing the symptoms of, or promoting health, includingbut not limited to of one or more of pain, inflammation, cough, cold,fever, flu, inflammation of the gastrointestinal tract, neoplasia,hyperthyroidism, hypercalcemia, hyperparathyroidism, parathyroidcarcinoma, indigestion, heartburn, irritable bowels, constipation,diarrhea, insomnia, dry mouth, halitosis, stained teeth, oral pain, lossof enamel, urge to smoke, fatigue, or malaise comprising administeringto a subject in need thereof an oral pharmaceutical composition suitablefor chewing, sucking, or buccal dissolution as described herein.

Another embodiment described herein is a method for treating, retardingthe progression of, prophylaxis of, delaying the onset of, ameliorating,or reducing the symptoms of cough, cold, or congestion comprising theadministration of a therapeutically effective amount of dextromethorphanhydrobromide comprising any one of the pharmaceutical compositionsdescribed herein to a subject with cough, wherein the administration issufficient to achieve a reduction of cough, congestion or cold relatedsymptoms.

In one aspect, after administration of any one the pharmaceuticalcompositions described herein, the subject experiences the side effectsdescribed herein at a rate of less than about 10%. In another aspect,the subject experiences the side effects described herein at a rate ofless than about 2%, about 5%, about 10%, about 15%, about 20%, about25%, about 30%, about 35%, about 45%, about 50%, about 60%, about 70%,about 80%, or about 90%.

Another embodiment described herein is a method for manufacturing theoral pharmaceutical composition comprising the steps of: (a) preparing agel fill composition comprising a first solution and a second solutionwherein: (i) the first solution comprises polyvinylpyrrolidone K30,orange flavor, citric acid, sucralose, acesulfame potassium, lycasin andwater, one or more excipients in one or more solvents and mixed at atemperature no greater than 55° C. until dissolved and clear; (ii) thesecond solution comprises polyethylene glycol 400, propylene glycol andlactic acid and mixed until dissolved and clear; where the compositioncomprises one or more film forming polymers, one or more plasticizers,one or more sweeteners, one or more excipients in one or more solvents;(iii) adding dextromethorphan hydrobromide and menthol to the secondsolution and mixing the first solution and heating to no greater than55° C. until dissolved; and (iv) combining the first solution with thesecond solution and purging with nitrogen; (b) preparing a gel masscomposition comprising one or more film forming polymers, one or moreplasticizers, one or more sweeteners, one or more excipients and one ormore solvents; (c) casting the gel composition into films or ribbonsusing heat-controlled drums or surfaces; and (d) forming a soft dosageform comprising a liquid matrix fill using rotary die encapsulationtechnology.

Another embodiment described herein is a method for manufacturing theoral pharmaceutical composition of claims comprising the steps of: (a)preparing a gel fill composition comprising a first gel fill solutionand a second gel fill solution, wherein (i) the first gel fil solutioncomprises one or more hydrophilic vehicle, sweetener, flavor, thymol, inone or more solvents and is mixed at a temperature between 30-50° C.until dissolved; (ii) the second gel fill solution comprises one or morehydrophilic vehicles and menthol and is mixed at a temperature between30-50° C. until dissolved; and (iv) combining the first gel fillsolution and the second gel fill solution, adding flavor and mixing forat least 25 minutes; (b) preparing a gel mass composition comprising oneor more film forming polymers, one or more plasticizers, one or moresweeteners, one or more excipients and one or more solvents; (c) castingthe gel composition into films or ribbons using heat-controlled drums orsurfaces; and (d) forming a soft dosage form comprising a liquid matrixfill using rotary die encapsulation technology.

Another embodiment described herein is a method for manufacturing theoral pharmaceutical composition of claims comprising the steps of: (a)preparing a gel fill composition comprising a first solution, a flavorsolution, and a sweetener solution wherein: (i) the first solutioncomprises one or more hydrophilic vehicles, thickening agents, flavors,and excipients and is mixed at a temperature between 30-70° C. untildissolved; (ii) the flavor solution comprises one or more hydrophilicvehicle and flavor and is mixed at a temperature between 30-70° C. untildissolved; (iii) the sweetener solution comprises one or more sweetenerin one or more solvents and nicotine and mixing until dissolved; and(iv) combining the first solution, flavor solution and sweetenersolution and mixing to homogenize; (b) preparing a gel mass compositioncomprising one or more film forming polymers, one or more plasticizers,one or more sweeteners, one or more excipients and one or more solvents;(c) casting the gel composition into films or ribbons usingheat-controlled drums or surfaces; and (d) forming a soft dosage formcomprising a liquid matrix fill using rotary die encapsulationtechnology.

Another embodiment described herein is a method for manufacturing anoral pharmaceutical composition comprising the steps of: (a) preparing agel fill composition comprising a color solution, a flavor solution anda gel solution wherein: (i) the color solution comprises one or morecolors and excipient in one or more solvents and mixed at a temperaturebetween 30-50° C. until dissolved; (ii) the flavor solution comprisesone or more of plasticizer, menthol and flavor and mixed at atemperature between 30-50° C. until dissolved; (iii) the gel solutioncomprises soaking one or more film forming polymer, plasticizer,sweeteners in one or more solvents, then heated at a temperature between30-70° C. until dissolved; (iv) combining the color solution, flavorsolution, and gel solution and adding bismuth subsalicylate and mixingat a temperature of 20-60° C. until dissolved; (b) preparing a gel masscomposition comprising one or more film forming polymers, one or moreplasticizers, one or more sweeteners, one or more excipients and one ormore solvents; (c) casting the gel composition into films or ribbonsusing heat-controlled drums or surfaces; and (d) forming a soft dosageform comprising a liquid matrix fill using rotary die encapsulationtechnology.

In another embodiment described herein, one or more of the oralpharmaceutical compositions described herein are contained and dispensedin a kit comprising a tamper evident packaging. The term “tamperevident” or “tamper resistant” refers to a packaging of any kind thatreadily displays or permits an individual to observe any physicalinterference or manipulation of said packaging. The tamper evidentpackaging provides reasonable evidence to consumers that tampering hasoccurred. The tamper evident packaging additionally contains appropriatelabelling statements describing the features and evidences of the tamperevident packaging. In one aspect, the tamper evident packagingcomprises: bottles, film wrappers, blister or strip packs, bubble packs,heat shrink bands or wrappers, foil, paper, or plastic pouches,container mouth inner seals, tape seals, breakable caps, sealed metaltubes or plastic heat-sealed tubes, sealed cartons, aerosol containers,cans including metal and composite materials, or any combinationthereof. The packaging may also comprise a dessicant and packing fillermaterial to prevent the contents from shifting or rattling. Thepackaging may also contain appropriate instructions for prescribing,instructions for use, warnings, or other appropriate information. Inanother aspect, the packaging may contain at least one daily regimen forthe oral pharmaceutical composition.

Another embodiment described herein is a kit for dispensing any of theoral pharmaceutical compositions described herein comprising: (a) atleast one oral pharmaceutical composition; (b) at least one moistureproof dispensing receptacle comprising blister or strip packs, analuminum blister, a transparent or opaque polymer blister with pouch,polypropylene tubes, colored blister materials, tubes, bottles, andbottles optionally containing a child-resistant feature, optionallycomprising a desiccant, such as a molecular sieve or silica gel; andoptionally (c) at least one daily regimen for the oral pharmaceuticalcomposition; and (d) an insert comprising instructions or prescribinginformation for the oral pharmaceutical composition. In one aspectdescribed herein, the kit is useful for treating pain, inflammation,cough, cold, sinusitis, throat or bronchial irritation, fever, flu,inflammation of the gastrointestinal tract, neoplasia, hyperthyroidism,hypercalcemia, hyperparathyroidism, parathyroid carcinoma, indigestion,heartburn, irritable bowels, constipation, diarrhea, insomnia, drymouth, halitosis, stained teeth, oral pain, loss of enamel, cessation ofurge to smoke, fatigue, or malaise according to any of the methodsdescribed herein.

It will be apparent to one of ordinary skill in the relevant art thatsuitable modifications and adaptations to the compositions,formulations, methods, processes, and applications described herein canbe made without departing from the scope of any embodiments or aspectsthereof. The compositions and methods provided are exemplary and are notintended to limit the scope of any of the specified embodiments. All ofthe various embodiments, aspects, and options disclosed herein can becombined in any and all variations or iterations. The scope of thecompositions, formulations, methods, and processes described hereininclude all actual or potential combinations of embodiments, aspects,options, examples, and preferences herein described. The exemplarycompositions and formulations described herein may omit any component,substitute any component disclosed herein, or include any componentdisclosed elsewhere herein. The ratios of the mass of any component ofany of the compositions or formulations disclosed herein to the mass ofany other component in the formulation or to the total mass of the othercomponents in the formulation are hereby disclosed as if they wereexpressly disclosed. Should the meaning of any terms in any of thepatents or publications incorporated by reference conflict with themeaning of the terms used in this disclosure, the meanings of the termsor phrases in this disclosure are controlling. Furthermore, theforegoing discussion discloses and describes merely exemplaryembodiments. All patents and publications cited herein are incorporatedby reference herein for the specific teachings thereof.

EXAMPLES Example 1

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Table 4. Compositioncomponents are set forth by weight percentage of the total weight of thecomposition. Such compositions may be encapsulated using rotary dieencapsulation as described herein.

Formulas 1 and 2 were the first shell formulations developed to achievefaster disintegration time and prevent crosslinking of the gelatin shellwith matrix fill components.

TABLE 4 Exemplary Liquisoft Composition Capsule Shell FormulationComponent Formula 1 Formula 2 Gelatin, 250 Bloom 24.3 — Gelatin, 150Bloom — 29.2 Gelatin, 100 Bloom  4.9 — Gelatin Hydrolysate — —Hydrolyzed Collagen — — Powdered Cellulose  1.9 — Maltitol — 25.7Glycerol 32.0 19.1 Xylitol  4.8 — Sucralose — — Citric Acid —  0.5Flavors —  0.5 Water 32.3 25.0 TOTAL 100% 100% VISCOSITY — 3497 cP

Example 2

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Table 5. Compositioncomponents are set forth by weight percentage of the total weight of thecomposition. Such compositions may be encapsulated using rotary dieencapsulation as described herein.

Formulas 3, 4 and 5 were developed to include citric acid, glycine andgelatin hydrolysate to inhibit crosslinking, 250 Bloom gelatin wassubstituted for 150 Bloom gelatin, and maltitol was used as the bulksweetener.

TABLE 5 Exemplary Liquisoft Composition Capsule Shell FormulationComponent Formula 3 Formula 4 Formula 5 Gelatin, 250 Bloom — — —Gelatin, 150 Bloom 29.0 29.0 24.5  Gelatin, 100 Bloom — — 4.9 GelatinHydrolysate  4.8 — — Hydrolyzed Collagen — — — Powdered Cellulose — — —Maltitol 18.1 18.1 — Glycerol 18.9 18.9 32.3  Xylitol — — 4.8 Mannitol 2.4  2.4 — Sucralose  0.2  0.2 0.2 Citric Acid  0.5  0.5 0.5 Glycine — 4.8 — Flavors — — — Water 25.8 25.8 32.5  TOTAL 100% 100% 100%VISCOSITY 4544 cP 2747 cP 1627 cP

Example 3

A dissolution study was performed using soft gel capsules comprising thepharmaceutical compositions shown in Tables 4 and 5. The compositions ofFormula 1 and Formula 2 served as controls. The time for completedissolution and average viscosity of each formula was recorded. Furthercompositions were formulated to achieve a higher viscosity.

TABLE 7 Exemplary Liquisoft Composition Complete Average DissolutionViscosity Formula (min) (cP) Formula 1 A mass of gel remains NT after 20minutes Formula 2 20 3497 Formula 3 19.5 4544 Formula 4 18 2747 Formula5 17.5 1627

Example 4

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Table 6. Compositioncomponents are set forth by weight percentage of the total weight of thecomposition. Such compositions may be encapsulated using rotary dieencapsulation as described herein.

Formula 6 had a higher viscosity due to a total of 39% gelatin.Application batches were made using Formula 6 and Formula 7 shellformulas as placebo and active fill formulations. Capsules wereevaluated but required further optimization to improve chewability.

TABLE 6 Exemplary Liquisoft Composition Capsule Shell FormulationComponent Formula 6 Formula 7 Gelatin, 250 Bloom — — Gelatin, 150 Bloom27.3  31.5 Gelatin, 100 Bloom 7.9 — Gelatin Hydrolysate 5.0 — HydrolyzedCollagen — — Powdered Cellulose — — Maltitol — 16.1 Glycerol 32.0  19.2Xylitol 4.8 — Mannitol — — Sucralose 0.2  0.2 Citric Acid 0.5  0.5Glycine —  5.0 Flavors — — Water 22.0  27.5 TOTAL 100% 100% VISCOSITY13,418 cP 5,748 cP

Example 5

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Table 7. Compositioncomponents are set forth by weight percentage of the total weight of thecomposition. Such compositions may be encapsulated using rotary dieencapsulation as described herein.

The composition of Formulas 8, 9, and 10 included increased amounts of100 Bloom gelatin to minimize shell toughness. As seen in Table 7,increased amounts of 100 Bloom gelatin resulted in decreased viscositybut encapsulation was unsuccessful. Formula 10 was revised further.

TABLE 7 Exemplary Liquisoft Composition Capsule Shell FormulationComponent Formula 8 Formula 9 Formula 10 Gelatin, 250 Bloom — — —Gelatin, 150 Bloom 14.2 18.7 19.8 Gelatin, 100 Bloom 14.2 12.5 13.1Gelatin Hydrolysate  4.9  4.9  5.2 Hydrolyzed Collagen — — — PowderedCellulose — — — Maltitol 15.7 16.7 18.8 Glycerol 18.9 20.2 20.6 Xylitol 0.5  0.5  5.2 Mannitol — — — Sucralose  0.5  0.5  0.2 Citric Acid  0.5 0.2  0.5 Glycine — — — Flavors — — — Water 30.6 25.8 16.6 TOTAL 100%100% 100% VISCOSITY 2,628 cP 1,899 cP 8,376 cP

Example 6

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Table 8. Compositioncomponents are set forth by weight percentage of the total weight of thecomposition. Such compositions may be encapsulated using rotary dieencapsulation as described herein.

Formula 10 was revised to increase the amount of water to 20%, resultingin Formula 11. Formula 11 was encapsulated, but was further revised toreduce the viscosity. Hence, Formula 12 was developed whereby the amountof water was increased to 22% and the total amount of gelatin waslimited to 31% resulting in a viscosity of approximately 4300 cP.Formula 12 was used for GMP batch manufacturing to evaluate thecombination product.

TABLE 8 Exemplary Liquisoft Composition Capsule Shell FormulationComponent Formula 11 Formula 12 Gelatin, 250 Bloom — — Gelatin, 150Bloom 22.7  18.9  Gelatin, 100 Bloom 9.7 8.1 Gelatin Hydrolysate 5.0 5.1Hydrolyzed Collagen — — Powdered Cellulose — — Maltitol 16.3  16.3 Glycerol 19.7  23.3  Xylitol 5.0 2.5 Mannitol — — Sucralose 0.2 0.2Citric Acid 0.5 0.5 Glycine — — Flavors 0.5 0.5 Water 20.2  24.8  TOTAL100% 100% VISCOSITY 13,226 cP 4,341 cP

Example 7

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Table 9. Compositioncomponents are set forth by weight percentage of the total weight of thecomposition. Such compositions may be encapsulated using rotary dieencapsulation as described herein.

Formula 13 was used for GMP batch manufacture.

TABLE 9 Exemplary Liquisoft Composition Capsule Shell FormulationComponent Formula 13 Gelatin, 250 Bloom — Gelatin, 150 Bloom 19.3 Gelatin, 100 Bloom 8.3 Gelatin Hydrolysate — Hydrolyzed Collagen 4.9Powdered Cellulose — Maltitol 16.8  Glycerol 24.0  Xylitol 2.6 Mannitol— Sucralose 0.2 Citric Acid 0.5 Glycine — Flavors 0.5 Water 22.7  TOTAL100% VISCOSITY —

Example 8

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Table 10.Composition components are set forth by weight percentage of the totalweight of the composition. Such compositions may be encapsulated usingrotary die encapsulation as described herein.

Formulas 14, 15, and 16 were the initial matrix prototypes fordextromethorphan hydrobromide (30 mg) and menthol (5 mg). Threedifferent taste-masking agents were tested: mannitol, thaumatin (Talin®)and glycyrrhizic acid salts (MagnaSweet®). Thaumatin resulted in themost effective taste masking of the dextromethorphan hydrobromide, butresulted in a hazy appearance.

TABLE 10 Exemplary Liquisoft Composition Matrix Formulation ComponentFormula 14 Formula 15 Formula 16 Propylene Glycol 8.1 8.1 8.1Polyethylene Glycol 400 25.4  25.4  25.4  Polyvinylpyrrolidone K30 1.51.5 1.5 Maltitol 50.0  50.0  50.0  Sucralose 0.6 0.6 0.6 Citric Acid 1.01.0 1.0 Lactic Acid 1.0 1.0 1.0 Sodium Citrate 1.0 1.0 1.0 Mannitol 3.0— — Thaumatin (Talin ®) — 3.0 — Glycyrrhizic acid salts — — 3.0(MagnaSweet ®) Water 5.0 5.0 5.0 Dextromethorphan 3.0 3.0 3.0Hydrobromide Menthol 0.5 0.5 0.5 TOTAL 100% 100% 100%

Example 9

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Table 11.Composition components are set forth by weight percentage of the totalweight of the composition. Such compositions may be encapsulated usingrotary die encapsulation as described herein.

Formulas 17, 18 and 19 were formulated with a reduced amount ofdextromethorphan hydrobromide (10 mg) and menthol (5 mg).

Thaumatin and glycyrrhizic acid salts were employed with the loweractive pharmaceutical ingredient dose, individually and as acombination. Thaumatin was found to be the most effective at tastemasking at the 10 mg dose and showed no precipitation (Formula 17).Thus, the glycyrrhizic acid salts were not further assessed for chemicalstability. Thus, Formula 19 was formulated using thaumatin and used forexcipient compatibility studies.

TABLE 11 Exemplary Liquisoft Composition Matrix Formulation ComponentFormula 17 Formula 18 Formula 19 Propylene Glycol 8.4 8.4 8.4Polyethylene Glycol 400 26.6  26.6  26.6  Polyvinylpyrrolidone K30 1.61.6 1.6 Maltitol 52.5  52.5  52.5  Sucralose 0.6 0.6 0.6 Citric Acid 1.61.6 1.0 Lactic Acid 1.6 1.6 1.0 Sodium Citrate 1.6 1.6 1.0 Mannitol — —— Thaumatin (Talin ®) 0.5 — 0.3 Glycyrrhizic acid salts — 0.6 0.2(MagnaSweet ®) Water 3.5 3.4 5.2 Dextromethorphan 1.0 1.0 1.0Hydrobromide Menthol 0.5 0.5 0.5 TOTAL 100% 100% 100%

Example 10

Formula 19 was used for excipient compatibility studies at stressedconditions (60° C. for 2 weeks) and the results are recorded in Table12. A 3% loss occurred in the sample taken on the day of fillcompounding and a 3% menthol loss occurred by the time the fill wasencapsulated.

TABLE 12 Exemplary Liquisoft Composition Formula 19 Assay (Talin-basedDextromethorphan fill) HBr Menthol Degradation Products T₀ 99.9% 97.4%Dextromethorphan: 0.01% 1 week at 100.0% 95.0% Dextromethorphan: 0.01%60° C. RRT 0.95: 0.03% 2 weeks at 99.7% 93.5% Dextromethorphan: 0.01%60° C. RRT 0.95: 0.03%

Example 11

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Table 11.Composition components are set forth by weight percentage of the totalweight of the composition. Such compositions were encapsulated usingrotary die encapsulation as described herein.

Formulas 20 and 21 were used as batch formulations for active lots.Formula 20 is the formulation for the amount per capsule. Formula 21 isthe formulation for the amount per batch.

TABLE 13 Exemplary Liquisoft Composition Matrix Formulation ComponentFormula 20 Formula 21 Propylene Glycol 8.4 8.4 Polyethylene Glycol 40025.6  26.6  Polyvinylpyrrolidone K30 1.6 1.6 Maltitol 52.7  52.7 Sucralose 0.6 0.6 Citric Acid 1.0 1.0 Lactic Acid 1.0 1.0 Sodium Citrate— — Mannitol — — Thaumatin (Talin ®) 0.5 0.5 Glycyrrhizic acid salts — —(MagnaSweet ®) Water 7.1 7.1 Dextromethorphan 1.0 1.0 HydrobromideMenthol 0.5 0.5 TOTAL 100% 100%

Example 12

Formula 21 was encapsulated and gel parameters were determined.Encapsulation was performed using a 6.2 inch die with cavity of a 1 gsquare chewel capsule with target fill weight of 960 mg. The medicinewas fed into the encapsulation machine using gravity feed from the 60 Ltank. Medium chain triglycerides (MCT) were utilized as lubricant duringencapsulation. The product was encapsulated at ambient temperatures anddried using a tumble drier. Gel parameters were recorded in Table 14.

TABLE 14 Exemplary Liquisoft Composition Encapsulation ParametersFormula 21 Matrix Formulation Gel Age (hrs) 4-72 Machine Die Speed (rpm)3.0 Die pressure (psi) 75 Target Ribbon Thickness 0.028 inches (Range0.025-0.031 inches) Fill weight (mg) Target: 960 mg Alert Limits:941-979 mg Control Limits: 912-1008 mg

Example 13

Batch analytical data for Formula 21 was determined and recorded inTable 15. Results were recorded at time, T=0 and again at time, T=1month at a temperature of 40° C. and 75% relative humidity (RH).

TABLE 15 Exemplary Liquisoft Composition Matrix Formulation Results at T= 1 months Results at Initial T = 0 40° C./75% RH Assay ResultsDextromethorphan Hbr 98.0% label claim 100.4% label claim Menthol 97.0%label claim 100.4% label claim Degradation Products ResultsDextromethorphan Hbr RRT 1.09: 0.05% RRT 1.09: 0.05% Total: 0.05% Total0.05% Menthol None Detected RRT 1.15: 0.1%; RRT 1.73: 0.2%, Total 0.03%Dissolution Study Results Dextromethorphan HBr Dextromethorphan HBr 15minutes: 99% 15 minutes: 99% 30 minutes: 98% 30 minutes: 98% 45 minutes:98% 45 minutes: 98% 60 minutes: 98% 60 minutes: 98%

Example 14

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Table 16.Composition components are set forth by weight percentage of the totalweight of the composition. Such compositions were encapsulated usingrotary die encapsulation as described herein.

TABLE 16 Exemplary Liquisoft Composition Weight Percentage Component (%)Capsule Shell Formulation Gelatin, 150 Bloom 19.3 Gelatin, 100 Bloom 8.3Hydrolyzed Collagen 4.9 Glycerol 24.0 Maltitol 16.8 Xylitol 2.6Sucralose 0.2 Citric Acid 0.5 Water 23.0 TOTAL 100% Matrix FillFormulation Propylene Glycol 8.4 Polyethylene Glycol 400 26.6Polyvinylpyrrolidone K30 1.6 Citric Acid 1.0 Lactic Acid 1.0 SodiumCitrate — Maltitol 52.7 Sucralose 0.6 Mannitol — Thaumatin (Talin ®) 0.5Glycyrrhizic acid salts — (MagnaSweet ®) Water 5.5 DextromethorphanHydrobromide 1.0 Menthol 0.5 TOTAL 100%

Example 15

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Table 17.Composition components are set forth by weight percentage of the totalweight of the composition. Such compositions may be encapsulated usingrotary die encapsulation as described herein.

TABLE 17 Exemplary Liquisoft Compositions Weight Percentage (%) EX EX EXEX EX EX Component 1 2 3 4 5 6 Capsule Shell Formulation Polymers 27 3235 39 40 55 Plasticizers 61.5 49.5 43.8 34.5 29.5 29.9 Polymer 1 0.1 0.70.7 1 1.3 Modifiers Solvent 9.4 17.4 20.4 25.4 28.4 13.4 Sweetener 0.50.5 0.2 0.5 0.5 0.1 Flavor 0.5 0.5 0.5 0.5 0.5 0.5 Coloring 0.1 0.1 0.10.1 0.1 0.1 TOTAL 100 100 100 100 100 100 Components and RelationalRatios Ratio Gelatin 0.44 0.64 0.80 1.11 1.33 1.83 to Plasticizer RatioGelatin 27.0 320.0 50.0 55.7 40.0 42.3 to Polymer Modifier Matrix FillFormulation Hydrophilic 21 27 31 38 47 55 Vehicle Sweeteners 68.5 61.555 52.75 34 31.5 Flavorings 1 4.1 2.5 3.24 5 5.5 Solvents 3.9 2.9 9.92.65 12.9 6.9 Coloring 0.1 0.1 0.1 0.1 0.1 0.1 Active 5.5 4.2 2.1 3.75 11 Pharmaceutical Ingredient (API) TOTAL 100% 100% 100% 100% 100% 100%Components and Relational Ratios Ratio API 0.06 0.04 0.02 0.04 0.01 0.01to remaining ingredients Ratio API 0.26 0.16 0.07 0.1 0.02 0.02 toHydrophilic Vehicle

Example 16

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Table 18.Composition components are set forth by weight percentage of the totalweight of the composition. Such compositions may be encapsulated usingrotary die encapsulation as described herein.

TABLE 18 Exemplary Liquisoft Compositions Weight Percentage (%) EX EX EXEX EX EX Component 1 2 3 4 5 6 Capsule Shell Formulation Gelatin 150B 1418 20 22 27 31 Gelatin 100B 8 10 9 12 8 19 Gelatin Hydrolysate 5 4 6 5 55 Glycerol 47 24 29 31 24.5 13.4 Maltitol 19 10 14.5 Xylitol 14.5 6.54.8 3.5 5 2 Citrate 1 0.1 0.7 — — 1.3 Lactate — — — 0.7 1 — Sucralose0.5 0.5 0.2 0.5 0.5 0.1 Solvent 9.4 17.4 20.4 25.4 28.4 13.4 Flavor 0.50.5 0.5 0.5 0.5 0.5 Coloring 0.1 0.1 0.1 0.1 0.1 0.1 TOTAL 100% 100%100% 100% 100% 100% Matrix Fill Formulation Propylene Glycol 2.5 5 6.5 79 6 Polyethylene Glycol 400 18 21 24 30 37 48 Polyvinylpyrrolidone K300.5 1 0.5 1 0.5 1 Citric Acid 0.33 1.37 0.83 1.08 1.67 2.75 Lactic Acid0.33 1.37 0.83 1.08 1.67 2.75 Sodium Citrate 0.33 1.37 0.83 1.08 1.67 —Maltitol 67 58 51.5 48.5 29.5 28.75 Sucralose 1 1 0.5 0.5 1.5 1.25Mannitol 0.5 — — — 3 — Talin — 2.5 — 3.75 — 1.5 MagnaSweet ® — — 3 — — —Solvent 3.9 2.9 9.9 2.65 12.9 6.9 Coloring 0.1 0.1 0.1 0.1 0.1 0.1Active Pharmaceutical 5.5 4.2 2.1 3.75 1 1 Ingredient (API) TOTAL 100%100% 100% 100% 100% 100%

Example 17

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Tables 19-21.Composition components are set forth by the quantity and weightpercentage of the total weight of the composition.

TABLE 19 Exemplary Liquisoft Shell Composition Weight QuantityPercentage Component (kg) (%) Gelatin, 150 Bloom Limed Bone, NF 79.519.3 Gelatin, 100 Bloom Limed Bone, NF 34.2 8.30 Hydrolyzed CollagenPeptan B 5000 HD 20.0 4.85 Glycerin, USP 98.7 23.95 Citric AcidAnhydrous, USP 2.16 0.52 Lycasin 80/55 69.0 16.75 Xylisorb 300, USP 10.82.62 Orange Flavor PB72 2.16 0.52 FD&C Yellow #6, Granular 0.08 0.02FD&C Red #40 0.02 0.0049 Sucralose, USP 0.84 0.20 Purified Water 94.622.96 TOTAL 412.06 100.0%

TABLE 20 Exemplary Liquisoft Fill Composition Weight Quantity PercentageComponent (mg) (%) Dextromethorphan HBr, USP 15.8* 1.6 L-MentholCrystals, USP 0.9 0.1 PEG 400, USP 195.0 19.5 Propylene Glycol, USP 80.08.0 Polyvinylpyrrolidone K30 12.0 1.2 Lactic Acid, USP 10.0 1.0 CitricAcid 10.0 1.0 γ-Cyclodextrin 22.0 2.2 Sucralose, USP 5.9 0.6 Acesulfamepotassium 6.0 0.6 Lycasin 80/55 551.4 55.1 Orange Flavor PB72 16.0 1.6Purified Water 75.0 7.5 TOTAL 1000.0 100.0% *Dextromethorphan HBr iscorrected for its impurity (impurity factor of 0.951).

TABLE 21 Exemplary Liquisoft Fill Composition Weight Quantity PercentageComponent (mg) (%) Dextromethorphan HBr, USP 15.8* 1.6 L-MentholCrystals, USP 2.5 0.3 PEG 400, USP 195.0 19.5 Propylene Glycol, USP 80.08.0 Polyvinylpyrrolidone K30 12.0 1.2 Lactic Acid, USP 10.0 1.0 CitricAcid 10.0 1.0 γ-Cyclodextrin 22.0 2.2 Sucralose, USP 5.9 0.6 Acesulfamepotassium 6.0 0.6 Lycasin 80/55 549.8 55 Orange Flavor PB72 16 16Purified Water 75 7.5 TOTAL 1000.0 100.0% *Dextromethorphan HBr iscorrected for its impurity (impurity factor of 0.951).

Example 18

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Tables 22-23.Composition components are set forth by weight percentage of the totalweight of the composition. Such compositions may be encapsulated usingrotary die encapsulation as described herein.

TABLE 22 Exemplary Liquisoft Shell Composition Weight Mass per QuantityPercentage capsule Component (kg) (%) (mg) Gelatin, 150 Bloom Limed79.50 19.9 111.2 Bone Gelatin, 100 Bloom Limed 34.20 8.6 47.8 BoneHydrolyzed Collagen 20.00 5.0 28.0 Peptan B 5000 HD Lycasin 80/55 67.6016.9 94.6 Glycerin, USP 98.70 24.7 138.0 Purified Water (I)* 82.00 20.5114.7 FD&C Yellow #6, Granular 0.08 0 0.1 FD&C Red #40 0.02 0 0.0Purified Water (II)** 1.00 0.3 1.4 Orange Flavor PB72 3.50 0.9 4.9Xylisorb 300, USP 10.00 2.5 15.1 Citric Acid Anhydrous, 2.10 0.5 3.0 USPSucralose, USP 0.84 0.2 1.2 TOTAL 399.54 100.0% 560.0

TABLE 23 Exemplary Liquisoft Fill Compositions Weight Weight QuantityPercentage Quantity Percentage Component (mg) (%) (mg) (%)Dextromethorphan 10.52 1.1 10.52 1.1 HBR L-Menthol 0.65 0.1 2.50 0.3 PEG400 210.00 21.0 210.00 21.0 Propylene Glycol 80.00 8.0 80.00 8.0 LacticAcid 10.00 1.0 10.00 1.0 Purified Water 55.00 5.5 55.00 5.5 Citric Acid10.00 1.0 10.00 1.0 Polyvinyl- 12.00 1.2 12.00 1.2 pyrrolidone K30Sucralose 5.90 0.6 5.90 0.6 Acesulfame 6.00 0.6 6.00 0.6 potassiumLycasin 80/55 579.93 58.0 578.08 57.8 Orange Flavor 20.00 2.0 20.00 2.0TOTAL 1000.0 100.0% 1000.0 100.0%

Example 19

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Tables 24-25.Composition components are set forth by weight percentage of the totalweight of the composition. Such compositions may be encapsulated usingrotary die encapsulation as described herein.

TABLE 24 Exemplary Liquisoft Shell Composition Weight QuantityPercentage Component (kg) (%) Gelatin, LB, 100 Bloom 114.0 27.76Hydrolyzed Collagen Peptan B 5000 HD 20.0 4.87 Lycasin 80/55 69.0 16.80Glycerin, USP 88.0 21.43 Propylene Glycol, USP 4.0 0.97 Purified Water(I) 89.0 21.67 FD&C Yellow #6, Granular 0.02616 0.01 FD&C Blue #10.01132 0.003 Purified Water (II) 1.0 0.24 Peppermint Oil 0.396 0.10Xylisorb 300, USP 10.2 2.48 Citric Acid Anhydrous, USP 2.16 0.53Sucralose, USP 0.84 0.20 Purified Water (III) 12.0 2.92 TOTAL 410.63100.0%

TABLE 25 Exemplary Liquisoft Fill Composition Weight Quantity PercentageComponent (kg) (%) Sorbitol Special 12.03 40.1 L-Menthol Flakes Pharma0.057 0.2 Glycerin, USP 12.45 41.5 Propylene Glycol, USP 0.60 2.0Polysorbate 20, NF 0.60 2.0 Purified Water 3.0 10.0 Citric Acid 0.0750.3 Polyvinylpyrrolidone K30 0.90 3.0 Sucralose, USP 0.15 0.5 Thymol,Crystal NF 0.0012 0 Eucalyptol 0.0276 0. Peppermint Oil 0.090 0.3 Methylsalicylate 0.018 0.1 TOTAL 29.9988 100.0%

Example 20

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Tables 26-27.Composition components are set forth by weight percentage of the totalweight of the composition. Such compositions may be encapsulated usingrotary die encapsulation as described herein.

TABLE 26 Exemplary Liquisoft Shell Composition Weight QuantityPercentage Component (kg) (%) Gelatin, LB, 150 Bloom 22 22.00 Gelatin,LB, 100 Bloom 10 10.00 Maltitol Syrup 17.25 17.25 Glycerin 99.7% 19.719.70 Titanium dioxide 2.1 2.10 Purified Water I 18.2 18.20 GelatinHydrolysate 5 5.00 Xylisorb 300 2.55 2.55 Citric Acid 0.54 0.54Sucralose 0.21 0.21 Purified Water II 3.15 3.15 Peppermint Oil 0.3 0.30TOTAL* 101 101.0 Components in the indented rows are mixed separatelyand then combined with the mixture of the other components. *Shellcontains 1% excess water to compensate vapor loss during vacuumdeaeration.

TABLE 27 Exemplary Liquisoft Fill Composition Weight Quantity PercentageComponent (kg) (%) Gelatin 70 Bloom LB 75.0 7.5 Glycerin 185.0 18.5Purified water I 107.0 10.7 Gelatin hydrolysate 90.0 9.0 Maltitol Syrup370.0 37.0 Glycine 50.0 5.0 Purified water II 30.0 3.0 Xylisorb 300 30.03.0 Menthol (crystal) 0.4 0.04 Peppermint oil 0.4 0.04 PEG-400 10.0 1.0Sucralose 2.0 0.2 Purified water III 30.2 3.0 Nicotine Polacrilex 20.02.0 (~20%)* TOTAL 1000.0 100.0% Components in the indented rows aremixed separately and then combined with the mixture of the othercomponents. *The amount of active is variable according to thecertificate of analysis (COA) of the Nicotine Polacrilex lot. Thedifference is accounted for by the adjusting the glycine amount.

Example 21

Exemplary capsule shell and matrix compositions useful for producingLiquisoft capsules as described herein are shown in Tables 28-29.Composition components are set forth by weight percentage of the totalweight of the composition. Such compositions may be encapsulated usingrotary die encapsulation as described herein.

TABLE 28 Exemplary Liquisoft Shell Composition Weight QuantityPercentage Component (kg) (%) Gel Component Mass (kg) % weight Gelatin,LB, 100 Bloom 52.64 12.82 Gelatin, LB, 150 Bloom 77.20 18.79 Glycerin91.84 22.36 TiO2 Mass 6.00 1.46 Gelatin hydrolysate 9.72 2.37 Maltitolsyrup 57.48 13.99 Purified Water I 86.60 21.08 FD&C Red #40 0.02 0.00D&C Red #33 0.02 0.01 Purified Water II * 2.00 0.49 Cherry Flavor **2.00 0.49 Xylisorb 300, USP 10.20 2.48 Citric acid anhydrous, USP 2.200.54 Sucralose, USP 0.84 0.2 Purified Water III *** 12.00 2.92%TOTAL**** 410.76 100.0% * Purified Water II serves to dissolvecolorants. ** Cherry Flavor is added to the gel on the day ofencapsulation. *** Purified Water III serves to dissolve sweeteners. Thesweetener solution is to be added to the gel on the day ofencapsulation. ****There is 2% extra water to compensate for vapor lossduring vacuum deaeration. Components in the indented rows are mixedseparately and then combined with the mixture of the other components.

TABLE 29 Exemplary Liquisoft Fill Composition Weight Quantity PercentageComponent (kg) (%) Glycerin 0.630 1.78 Gelatin hydrolysate 0.630 1.78Gelatin, 70B LB 0.630 1.78 Sorbitol Special 9.450 26.72 Xylisorb 3000.950 2.69 Propylene glycol 1 2.050 5.80 PEG-400 0.320 0.90 Sucralose0.063 0.18 Purified Water 1* 3.670 10.38 FD&C Red #40 0.002 0.00 FD&CRed #33 0.002 0.01 Purified Water 2 0.079 0.22 Menthol (crystal) 0.0160.04 Peppermint oil 0.016 0.04 Propylene glycol 2 0.320 0.90 Simethicone0.001 0 Bismuth Subsalicylate 16.540 46.77 TOTAL** 35.37 100.0% *Thereis 1% extra water to compensate for vapor loss during vacuum deaeration.**Theoretical total batch weight is 35.02 kg after excluding 0.35 kgadditional water. Nitrogen blanketing is maintained throughout thecompounding process and storage period. Components in the indented rowsare mixed separately and then combined with the mixture of the othercomponents.

What is claimed is:
 1. An oral pharmaceutical composition suitable forchewing, sucking, or buccal dissolution comprising a soft shellencapsulating a liquid matrix, the shell consists of: (a) about 20% toabout 50% by weight of the shell of one or more of gelatin, partiallyhydrolyzed gelatin, or hydrolyzed gelatin; (b) about 30% to about 50% byweight of the shell of glycerol, maltitol, mannitol, xylitol, lycasin,or combinations thereof; (c) about 0.25% to about 1% by weight of theshell of citric acid, acetic acid, lactic acid, malic acid, tartaricacid, or combinations thereof; (d) about 0.1% to about 5% by weight ofthe shell of sucralose, aspartame, stevia, acesulfame potassium,xylitol, or combinations thereof; and (e) about 10% to about 40% waterby weight of the shell; and the liquid matrix consists of: (f) about 20%to about 90% by weight of the matrix of polypropylene glycol,polyethylene glycol 400, polyvinylpyrrolidone, gylcerol, sorbitol,maltitol, xylitol, maltitol, or combinations thereof; (g) about 0.1% toabout 10% by weight of the matrix of thaumatin, glycyrrhizic acid salts,acesulfame potassium, acesulfame salts, sucralose, aspartame, stevia, orcombinations thereof; (h) about 0.01% to about 5% by weight of thematrix of citric acid, lactic acid, sodium citrate, orange flavor,cherry flavor, eucalyptol, peppermint oil, methyl salicylate, glycine,or combinations thereof; (i) about 1% to about 15% water by weight ofthe matrix; and (j) about 0.25% to about 50% by weight of the matrix ofone or more active pharmaceutical ingredients.
 2. The composition ofclaim 1, wherein the ratio of the active pharmaceutical ingredient to acombined weight percentage of the hydrophilic vehicle, flavor,sweetener, solvent and excipient is about 1:0.5 to about 1:500.
 3. Thecomposition of claim 1 wherein the shell further comprises about 0.01%to about 10% by weigh of the shell of one or more flavors, colors, oropacifiers.
 4. The composition of claim 1, wherein the one or moreactive pharmaceutical ingredients comprises one or more ofdextromethorphan hydrobromide, menthol, thymol, nicotine, nicotinepolacrilex, bismuth subsalicylate, NSAIDS, or combinations thereof. 5.The composition of claim 1, wherein the active pharmaceutical ingredientcomprises one or more of: astemizole, azelastine, azatadine,brompheniramine, carbinoxamine, cetirizine, chlorpheniramine,clemastine, cyproheptadine, desloratadine, dexbrompheniramine,dexchlorpheniramine, diphenhydramine, fexofenadine, hydroxyzine,levocetirizine, loratadine, phenindamine, pheniramine, phenyltoloxamine,promethazine, pyrilamine, terfenadine, tripelennamine, triprolidine,acetyl dihydrocodeine, benproperine, benzonatate, benzylmorphine,bibenzonium bromide, butamirate, butorphanol, carbetapentane,chlophedianol, clobutinol, clofedanol, cloperastine, codeine,dextromethorphan, dextromethorphan hydrobromide, diacetylmorphine,dibunate, dihydrocodeine, dimemorfan, dimethoxanate, diphenhydramine,dropropizine, droxypropine, ethylmorphine, fedrilate, glaucine,hydrocodone, hydromorphone, isoaminile, laudanum, levodropropizine,levomethadone, levopropoxyphene, meprotixol, methadone, morclofone,nepinalone, nicocodine, nicodicodine, normethadone, noscapine, oxeladin,oxolamine, pentoxyverine, pholcodine, pipazetate, piperidione,prenoxdiazine, tipepidine, zipeprol, acetylcysteine, althea root,ambroxol, antimony pentasulfide, bromhexine, carbocisteine, cineole,combinations, combinations, creosote, dembrexine hydrochloride,domiodol, dornase alfa, eprazinone, erdosteine, guaiacolsulfonate,guaifenesin, hederae helicis folium, ipecacuanha, letosteine, levoverbenone, mannitol, mesna, neltenexine, potassium iodide, senega,sobrerol, stepronin, tiopronin, tyloxapol, pseudoephedrine, cetirizine,loratadine, fexofenadine, diphenhydramine, levocetirizine,desloratadine, phenol, ethanol, thymol, eucalyptol, ethanol, methylsalicylate, chlorhexidine gluconate, cetylpyridinium chloride,hexetidine, triclosan, hydrogen peroxide, domiphen bromide, bismuthsubsalicylate, loperamide hydrochloride, aluminum hydroxide, magnesiumhydroxide, magnesium aluminum silicate simethicone, aluminum carbonate,calcium carbonate, sodium bicarbonate, hydrotalcite, magaldrate,cimetidine, famotidine, nizatidine, ranitidine, lansoprazole,omeprazole, esomeprazole, rabeprazole, pantoprazole, dexlansoprazole,diphenoxylate, dicyclomine, loperamide, rifaximin, alosetron,cholestyramine, linaclotide, lubiprostone, methylcellulose,polycarbophil, psyllium, mineral oil, glycerol, docusate sodium, sodiumbicarbonate, sodium phosphate, magnesium citrate, magnesium oxide,magnesium sulfate, bisacodyl, sennosides, senna, castor oil,alclometasone, amcinonide, beclometasone, betamethasone, budesonide,ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol,cortivazol, deflazacort, deoxycorticosterone, desonide desoximetasone,dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone,fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone,fluperolone, fluticasone, fluticasone propionate, fluprednidene,formocortal, halcinonide, halometasone, hydrocortisone aceponate,hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,medrysone, meprednisone, methylprednisolone, methylprednisoloneaceponate, mometasone furoate, paramethasone, prednicarbate, prednisone,prednisolone, prednylidene, rimexolone, tixocortol, triamcinolone,ulobetasol, 5-fluorouracil, 5-fluorodeoxyuridine, capecitabine, calciumsupplements, calcimimetics, cinacalcet, nicotine, nicotine polacrilex,bupropion, varenicline, disulfiram, calcium carbimide, acamprosate,naltrexone, buprenorphine, methadone, levacetylmethadol, lofexidine,betahistine, cinnarizine, flunarizine, acetylleucine, gangliosides,ganglioside derivatives, tirilazad, riluzole, xaliproden, hydroxybutyricacid, amifampridine, doxylamine, diphenhydramine hydrochloride,melatonin, 1-theanine, monofluorophosphate, lactoferrin, lysozyme,lactoperoxidase, glucose oxidase, mutanase, dextranase, glycerol,carbamide peroxide, sodium bicarbonate, hydrated silica, silicondioxide, polyvinylpyrrolidone, potassium nitrate, sodiummonofluorophosphate, sodium tripolyphosphate, strontium chloride,potassium nitrate, strontium acetate, strontium chloride, calcium sodiumphosphosilicate, benzocaine, lidocaine, clove oil, sodium bicarbonate,citric acid, tartaric acid, aspirin, ibuprofen, aceclofenac, acemetacin,aloxiprin, azapropazone, benorilate, bromfenac, carprofen, celecoxib,choline magnesium salicylate, diclofenac, diflunisal, etodolac,etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, indometacin,ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, meclofenamicacid, mefenamic acid, meloxicam, metamizole, methyl salicylate,magnesium salicylate, nabumetone, naproxen, nimesulide, paracetamol,oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicylsalicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenicacid, tolmetin, valdecoxib, acetylsalicylic acid, aloxiprin,aminophenazone, anilides, benorilate, benzomorphan derivatives,bezitramide, bucetin, buprenorphine, butorphanol, carbasalate calcium,choline salicylate, codeine, dextromoramide, dextropropoxyphene,dezocine, diamorphine, diflunisal, dihydrocodeine, dihydrocodone,dihydromorphine, di phenylpropylamine derivatives, dipyrocetyl,ethenzamide, fentanyl, floctafenine, flupirtine, glafenine, guacetisal,hydrocodone, hydrocodone bitartrate, hydromorphone, hydromorphonehydrochloride, imidazole salicylate, ketobemidone, metamizole sodium,methadone, morphinan derivatives, morphine, morphine sulphatepentahydrate, morphine-6-glucuronode, morpholine salicylate, nalbuphine,natural opium alkaloids, nefopam, nicomorphine, nifenazone,non-steroidal anti-inflammatory drugs (NSAID), norhydrocodone,noroxycodone, opioids, opium, oripavine derivatives, oxycodeine,oxycodone, oxycodone hydrochloride, oxymorphone, papaveretum,pentazocine, pethidine, phenacetin, phenazocine, phenazone,phenylpiperidine derivatives, piritramide, potassium salicylate,propacetamol, propyphenazone, pyrazolones, rimazolium, salicylamide,salicylic acid derivatives, salsalate, sodium salicylate, tapentadol,tilidine, tramadol, viminol, ziconotide, caffeine, taurine, Ginkobiloba, glucuronolactone, inositol, niacin, niacinamide, D-pantothenol,Panax ginseng root extract, pyridoxine HCl, vitamin B12, cyanocobalamin,riboflavin, guarana, L-carnitine, vitamin A (retinol), B1 (thiamine), B2(riboflavin), B complex, B6 (pyridoxine), B12 (cobalamin), C (ascorbicacid), D (cholecalciferol), E (tocopherol), F (linoleic acid), G, H(biotin), and K, and choline, folic acid, inositol, niacin, pantothenicacid, para-aminobenzoic acid, terpenoids (e.g., carotenoid terpenoidsand non-carotenoid terpenoids), herbal supplements, homeopathicsupplements, glandular supplements, polyphenolics, flavonoidpolyphenolics, phenolic acids, curcumin, resveratrol, lignans,glucosinolates, isothiocyanates, indoles, thiosulfinates, phytosterols,anthraquinones, capsaicin, piperine, chlorophyll, betaine, oxalic acid,acetyl-L-carnitine, allantoin, androstenediol, androstendione, betaine(trimethylglycine), caffeine, calcium pyruvate (pyruvic acid),carnitine, carnosine, carotene, carotenoid, choline, chlorogenic acid,cholic acid, chondroitin sulfate, chondroitin sulfate, cholestan,chrysin, coenzyme Q10, conjugated linoleic acid, corosolic acid,creatine, dehydroepiandrosterone, dichlorophen, diindolymethane,dimethylglycine, dimercapto succinic acid, ebselen, ellagic acid,enzymes, fisetin, formononetin, glucaric acid (glucarate), glucosamine(HCl or sulfate), glucosamine (N-acetyl), glutathione, hesperidine,hydroxy-3-methylbutyric acid, 5-hydroxytryptophan, indole-3-carbinol,inositol, isothiocyanates, linolenic acid-gamma, lipoic acid (alpha),melatonin, methylsulfonylmethane, menthol, minerals, naringin,pancreatin, para-aminobenzoic acid, paraben (methyl or propyl),phenolics, phosphatidylcholine, phosphatidylserine, phospholipids,phytosterols, progesterone, pregnenolone, omega-3 fatty acids,quercetin, resveratrol, D-ribose, rutin, S-adenosylmethionine, salicylicacid, sulforaphane, tartaric acid, taxifolin, tetrahydropalmatine,theophyline, theobromine, tigogenin, troxerutin, tryptophan, tocotrienol(alpha, beta, and gamma), zeaxanthin, Gingko biloba, ginger, cat's claw,hypericum, Aloe vera, evening primrose, garlic, Ginseng, capsicum, dongquai, ginseng, feverfew, fenugreek, echinacea, green tea, marshmallow,saw palmetto, tea tree oil, fish oil, psyllium, kava-kava, licoriceroot, Mahonia aquifolium, hawthorne, tumeric, witch Hazel, yohimbe,aleurain, mistletoe, bilberry, bee pollen, peppermint oil,beta-carotene, genistein, lutein, lycopene, polyphenols, Bifidobacteriuminfantis 35624, Bifidobacterium lactis HN019, Lactobacillus reuteriATCC55730, Lactobacillus rhamnosus, Lactobacillus casei DN-114 001,Bifidobacterium lactis Bb-12, or mixtures or combinations thereof. 6.The composition of claim 1, wherein the shell consists of: (a) about 20%gelatin, 150 Bloom; (b) about 9% gelatin, 100 Bloom; (c) about 5%hydrolyzed collagen; (d) about 17% lycasin; (e) about 25% glycerin; (f)about 0.5% citric acid; (g) about 2.5% about xylitol; (h) about 0.2%sucralose; and (i) about 21% water; and the liquid matrix consists of:(j) about 21% polyethylene glycol 500; (k) about 8% propylene glycol;(l) about 1% polyvinylpyrrolidone K30; (m) about 58% lycasin; (n) about1% citric acid; (o) about 1% lactic acid; (p) about 0.6% sucralose; (q)about 0.6% acesulfame potassium; (r) about 5% water; (s) about 1%dextromethorphan hydrobromide; and (t) about 0.1% menthol.
 7. Thecomposition of claim 1, wherein the shell consists of: (a) about 27%gelatin, 100 Bloom; (b) about 5% hydrolyzed collagen; (c) about 17%lycasin; (e) about 21% glycerin; (f) about 1% propylene glycol; (g)about 0.5% citric acid; (h) about 2.5% xylitol; (i) about 0.8%sucralose; (j) about 0.1% peppermint oil; (k) about 24% water; and theliquid matrix consists of: (l) about 42% glycerin; (m) about 2%propylene glycol; (n) about 3% polyvinylpyrrolidone K30; (o) about 40%sorbitol; (p) about 0.3% citric acid; (q) about 0.5% sucralose; (r)about 0.1% eucalyptol; (s) about 0.3% peppermint oil; (t) about 10%water; (u) about 0.004% thymol; and (v) about 0.2% menthol.
 8. Thecomposition of claim 1, wherein the shell consists of: (a) about 22%gelatin, 150 Bloom; (b) about 10% gelatin, 100 Bloom; (c) about 5%gelatin hydrolysate; (d) about 20% glycerin; (e) about 17% maltitol; (f)about 0.5% citric acid; (g) about 2.6% xylitol; (h) about 0.2%sucralose; (i) about 0.3% peppermint oil; and (j) about 21% water; andthe liquid matrix consists of: (k) about 1% polyethylene glycol 400; (l)about 19% glycerin; (m) about 3% xylitol; (n) about 37% maltitol; (o)about 5% glycine; (p) about 0.2% sucralose; (q) about 0.04% menthol; (r)about 0.04% peppermint oil; (s) about 17% water; and (t) about 2%nicotine polacrilex.
 9. The composition of claim 1, wherein the shellconsists of: (a) about 19% gelatin, 150 Bloom; (b) about 13% gelatin,100 Bloom; (c) about 2% gelatin hydrolysate; (d) about 22% glycerin; (e)about 14% maltitol; (f) about 0.5% citric acid; (g) about 2.5% xylitol;(h) about 0.2% sucralose; and (i) about 29% water; and the liquid matrixconsists of: (j) about 1% polyethylene glycol 400; (k) about 2%glycerin; (l) about 6% propylene glycol; (m) about 27% sorbitol; (n)about 3% xylitol; (o) about 0.2% sucralose; (p) about 0.04% menthol; (q)about 0.04% peppermint oil; (r) about 11% water; and (s) about 47%bismuth subsalicylate.
 10. A kit for dispensing the oral pharmaceuticalcomposition of claim 1, the kit comprising: (a) at least one oralpharmaceutical composition; (b) at least one moisture proof dispensingreceptacle selected from blister or strip packs, tubes, or bottles; and(c) an insert or label comprising instructions or prescribinginformation for the oral pharmaceutical composition.
 11. The kit ofclaim 10, that is useful for treating pain, inflammation, cough, cold,chest congestion, nasal congestion, sinusitis, throat or bronchialirritation, allergies, fever, flu, inflammation of the gastrointestinaltract, sour stomach, neoplasia, hyperthyroidism, hypercalcemia,hyperparathyroidism, parathyroid carcinoma, indigestion, heartburn,irritable bowels, constipation, diarrhea, insomnia, dry mouth, mouthodor, halitosis, stained teeth, oral pain, loss of enamel, nicotinedesire, cessation of urge to smoke, fatigue, or malaise.